Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1
Reactant: N#CCCn1ccc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: N#CCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
2,2,2-Trifluoroethylisothiocyanate (3.4 g.) was added to a solution of 3-amino-1-(2-cyanoethyl)-pyrazole (2.72 g.) in acetonitrile (10 ml.) and the solution left at room temperature for 18 hours. The mixture was was evaporated to dryness and the residue recrystallised from ethanol to give 3-[3-(2,2,2-trifluoroethyl)thioureido]-1-(2-cyanoethyl)pyrazole, m.p. 164°-165°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30]O.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30][N:36]1[CH2:37][CH2:38][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35]1
Reactant: OCc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 63 %

Procedure:
The desired compound was prepared according to the procedure of Example B191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol trifluoroacetate and tert-butyl piperazine-1-carboxylate as the starting materials in 63% yield. LCMS for C28H34ClN6O2(M+H)+: m/z=521.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of commercially available 5-bromo-2-benzofuran-1(3H)-one (50 g, 0.235 mol) in trifluoromethanesulfonic acid (400 mL) was added N-iodosuccinimide (55.5 g, 0.247 mol). The resulting mixture was stirred at room temperature overnight, then poured slowly into ice water (2 L), filtered and the filtrate extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to give 5-bromo-4-iodo-2-benzofuran-1(3H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[CH3:10][C:11]([CH3:13])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH:11]([CH3:13])[CH3:10])[CH3:5]
Reactant: CNc1ccccc1Br
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)N(C)c1ccccc1Br
Reaction time: 72 h

Procedure:
To a solution of 2-bromo-N-methylaniline (2.07 g, 11.22 mmol), in dichloroethane (45 mL) was added acetone (1.31 g, 22.5 mmol), AcOH (4.04 g, 67.32 mmol) and Na(OAc)3BH (7.14 g, 33.66 mmol) sequentially at RT. The mixture was stirred for 72 h. The reaction was cooled with ice bath, and 2M NaOH (100 mL) was added slowly, then stirred for 5 min. The organic layer was separated, washed with brine dried and solvent removed. The crude product contained a mixture of 2:1 ratio of Compound 219 and starting material. This mixture was used as is in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10]([NH:22][CH3:23])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[C:10]([NH:22][CH3:23])[N:9]=[C:8]2[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: CNc1nc(-c2cncc(Br)c2)c2cc(OC)c(OC)cc2n1
Reactant: CSc1ccc(OB(O)O)cc1
Product: CNc1nc(-c2cncc(-c3ccc(SC)cc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 105.2 %

Procedure:
Starting from 375 mg of 4-(5-bromo-3pyridyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 76 and 225 mg of 4-methylthiophenylboric acid, 440 mg of the title compound was obtained as pale yellow crystals in the same manner as in Example 48.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[CH2:4][C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:18]([O:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])=[C:12]([CH2:15][O:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6].[N:32]([O-])=[O:33].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:31])[C:4](=[N:32][OH:33])[C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:18]([O:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])=[O:19])=[C:12]([CH2:15][O:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)CC(=O)CCl)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2.57 g of pivaloyloxymethyl 7-(4-chloro-3-oxobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylate were dissolved in 25 ml of acetic acid, and then 409 mg of sodium nitrite were added, little by little, at room temperature to the solution, after which the mixture was stirred for 30 minutes. The mixture was then diluted with 200 ml of ethyl acetate, washed three times with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure. The residue was twice subjected to azeotropic distillation using toluene and the resulting residue was dried, giving 2.7 g of the title compound as a foamy solid.
Reaction SMILES: [Na+].[CH2:2]([S:6]([NH-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][CH3:5].CC(C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:23])=[CH:17][CH:16]=1
Reactant: CCCCS([NH-])(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
1-butanesulfonamide sodium salt (9.1 g, 57 mmole) was dissolved in water (40 ml) and acetone (40 ml) was added. To the resulting mixture was added dropwise 40 ml of acetone containing 4-chlorophenyl isocyanate (8.6 g). After two hours solid was removed from the reaction mixture by filtration. The solid was washed with water and the combined filtrate was treated with 1N HCl (57 ml). After about one hour, precipitate was collected from the filtrate and washed with water. After drying at 65° C. under vacuum, 10.7 g of product were obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])S[CH2:4][CH2:3]1.OO.[S:19]([O-:22])(O)=[O:20].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:19](=[O:22])(=[O:20])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2C
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2C
Yield: 98 %

Procedure:
A 30-ml eggplant type flask was charged with 0.75 g (3.2 mmol) of the 4,5,8-trimethylthiochroman-6-carboxylic acid, 1.1 g (9.5 mmol) of 30% hydrogen peroxide and 1 ml of acetic acid, and the mixture was allowed to react at 100° C. for 2 hours. The reaction mixture was poured into a sodium hydrogensulfite aqueous solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the solvent was distilled off to give 0.76 g (yield 98%) of 4,5,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li][CH3:17]>C(OCC)C.O>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:17])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Li]C
Reactant: Cc1sc(C(=O)O)cc1-c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cc(-c2ccccc2)c(C)s1
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-4-phenyl-thiophene-2-carboxylic acid (1.50 g, 6.87 mmol) in diethyl ether (100 mL) MeLi (7 mL, 1.5 M in diethyl ether) is added at 5° C. The mixture is stirred at it for 90 min before another portion of MeLi (1 mL) is added. Stirring is continued for 1 h. The mixture is diluted with water and extracted with EA. The organic extracts are evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(5-methyl-4-phenyl-thiophen-2-yl)-ethanone (490 mg) as a colourless oil, LC-MS: tR=1.00 min, [M+1]+=217.10; 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.48-7.33 (m, 5H), 2.54 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[N:27]1[C@H:26]([CH3:25])[CH2:30][O:29][C:28]1=[O:31]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)c(Cl)c3)CC2)c(C)c1
Yield: 16.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.7 g) described in Preparation Example 70 and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (288 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].[C:22](Cl)(Cl)=[S:23]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([N:16]=[C:22]=[S:23])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(N=C=S)c(-c2ccc(F)c(F)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3,4-difluorophenyl)-5-methylpyridin-2-amine (0.6 g, 2.7 mmol) in dichloromethane (15 mL) was added a solution of sodium bicarbonate (2.3 g, 26.7 mmol) in water (25 mL) followed by a solution of thiophosgene (0.25 mL, 3.2 mmol) in dichloromethane (1 mL) and the mixture stirred for 15 minutes. The phases were separated and the organic phase was dried with sodium sulfate and the solvent was evaporated in vacuo to afford the title compound was obtained as a crystalline yellow solid (0.7 g, 100%).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:21])[CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.N1C=CC=CC=1SC(=O)CC[C:32]1[CH2:37][CH2:36][CH2:35][CH2:34]C=1>>[CH:34]1([C:8](=[O:21])[CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:35][CH2:36][CH2:37][CH2:32]1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Reactant: COc1ccc2c(c1)CCC2CC(=O)Sc1ccccn1
Product: COc1ccc2c(c1)CCC2CC(=O)C1CCCC1

Procedure:
The title compound was prepared as described in Step 4 of Example A(13), where (5-Methoxy-indan-1-yl)-thioacetic acid S-pyridin-2-yl ester (from Step 3) was substituted in place of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester. 1H NMR (CDCl3): δ 1.55-1.85 (br m, 9H), 2.39 (m, 1H), 2.60 (dd, 1H, J=17.2, 8.6 Hz), 2.80-2.92 (m, 4H), 3.59 (m, 1H), 3.78 (s, 3H), 6.70 (d, 1H, J=8.3 Hz), 6.77 (s, 1H), 7.02 (d, 1H, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Cl
Solvent: CO
Product: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Nc1cccc(Br)c1

Procedure:
A solution of 3-bromoaniline (227 mL, 0.020 mol) and 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (2.02 g, 0.0083 mol; prepared by analogy with the methods described in WO97/34890 and Wiley, R P H, and Slaymaker, S. C. J. Am. Chem. Soc (80) 1385 (1958)) in methanol (50 mL) was heated at reflux for 40 hours, cooled and concentrated. The residue was acidified with aqueous hydrochloric acid (1M, 200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water and brine, dried with magnesium sulphate, evaporated and the residue chromatographed on silica gel using dichloromethane-diethyl ether (gradient from 100:0 to 95:5 v/v) as eluent to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:9][S-:10].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([S:10][CH3:9])[CH:7]=1
Reactant: C[S-]
Reactant: Clc1cnnc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cnnc(Cl)c1
Yield: 76 %

Procedure:
3,5-Dichloropyridazine, which is known in the art, (2.0 g, 0.0135 moles) and sodium thiomethoxide (1.14 g, 0.0162 moles) were stirred in THF (50 mL) at RT under N2 for 2 h. The mixture was then poured into water and extracted 2×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 3-chloro-5(methylthio)pyridazine (1.64 g, 76% yield) as a brown solid, mp=98° C.-100° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: COCCCN
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: COCCCNC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with 3-methoxy-propylamine gives “A94”; method 1: HPLC/MS: 1.30 min, [M+H]=406;
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31](Cl)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCCN1CCCCC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCCCN2CCCCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-piperidin-1-yl-propan-1-ol (0.85 mmol, 121 mg) in THF at room temperature, NaH (1.2 mmol, 29 mg) was added and stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.42 mmol, 150 mg) was added. The resulting mixture was stirred at 50-55° C. over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 4-(4-Benzyloxy-phenyl)-3-butyl-6-(3-piperidin-1-yl-propoxy)-pyridazine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1.O>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: COCc1nccc(Cl)n1
Reactant: CNC
Solvent: CCO
Solvent: O
Product: COCc1nccc(N(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 33% w/w solution of dimethylamine in ethanol (45 ml) was added dropwise to a stirred solution of 2-methoxymethyl-4-chloropyrimidine (7.54 g) in ethanol (100 ml), cooled over an ice bath. The mixture was allowed to warm to room temperature, and left to stand for 16 hours. After stripping, the residue was treated with water (100 ml), and extracted with chloroform. The extracts were dried (K2CO3) and stripped to give 2-methoxymethyl-4-dimethylaminopyrimidine (7.41 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.C1C(=O)N([Br:36])C(=O)C1.O>CN(C=O)C>[Br:36][C:16]1[C:17]2[N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:12]=2[C:13]([O:18][CH3:19])=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (148.1 mg) obtained in Step A of Example 39 in DMF (5 mL) was added NBS (77 mg) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (161 mg).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][CH:9]([CH3:26])[CH2:10][C@@H:11]([NH3+:25])[B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1.[C:27]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C@H:35]([C:39](=[O:40])[NH:25][C@H:11]([B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1)[CH2:10][CH:9]([CH3:26])[CH3:8])[CH:36]([CH3:37])[CH3:38])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)C[C@@H]([NH3+])B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described in step B of example 1 but using (S)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylammonium trifluoroacetate ((C) in Synthetic Scheme 1) (for preparation see Kettner, C. A. and Shenvi, A. B. J. Biol. Chem. 1984, 259, p. 15106-15114 and Matteson, D. S. and Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, p. 5241-5242) (2.395 g, 6.32 mMol), Boc-L-valine (1.373 g, 6.32 mMol), TBTU (2.23 g, 6.95 mMol, 1.1 equiv), DIEA (3.3 mL, 18.95 mMol, 3.0 equiv) and DMF (24 mL).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:2]([NH:1][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1ccc(Cl)cc1

Procedure:
9.6 g of 3-amino-3-(4-chlorophenyl)propionic acid are dissolved in 200 ml of dioxane and about 50 ml of 1N NaOH in order to reach pH=10.5-11.5. The medium is cooled to +5° C. and 6.34 ml of phenylacetyl chloride are then gradually added, while maintaining the mixture at pH=10.5-11.5 and at a temperature of between +5° C. and +10° C. Stirring is continued for 1 and a half hours and the medium is then concentrated to one-half before diluting with 500 ml of water. The resulting mixture is washed twice with EtOAc and then acidified to pH=1-2 by addition of 6N HCl. The solid is drained, washed with water and dried to give 14 g of the expected compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: [NH3+]O
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 49.4 %

Procedure:
10 g (49.0 mmol) of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.1 g (58.8 mmol) of hydroxylammonium chloride and 11.9 ml (147 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into 50 ml of water, and extracted with 100 ml and 50 ml of ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by chromatography with methylene chloride, yielding 5.3 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime as a white solid with a melting point of 62-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 3.84 (s, 3H), 6.93(E)/6.99(Z) (d, 2H), 7.45(E)/7.55(Z) (d, 2H), 8.78 (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=1:1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetic acid 3-hydroxyphenyl ester (5.0 g, 32.86 mmol) and potassium carbonate (6.8 g, 49.3 mmol) in DMF (40 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (6.8 g, 32.86 mmol) at RT. The reaction mixture is stirred for 3 h at RT followed by 24 h at 70° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 20% ethyl acetate in hexane to yield acetic acid-3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ester as a clear oil.