Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[S:13][C:14]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=3[C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:14]2[S:13][C:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=3)(=[O:11])=[O:10])=[C:16]([CH3:17])[C:15]=2[CH:18]=1
Reactant: COc1ccc(S(=O)(=O)c2sc3ccc(Cl)cc3c2C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)c2ccc(=O)[nH]n2)sc2ccc(Cl)cc12
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-pyridazine, (0.55 mmol, 197 mg), conc. HCl (1 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting yellow precipitate, 6-(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one, was collected (29%, 55 mg); mp 258° C.-259° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH:21]=[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:20]
Reactant: COc1cccc(C2CCCCC2=O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCCCC1c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Combine 2-(3-methoxyphenyl)-cyclohexanone (5.0 g, 24.5 mmol), carbethoxymethylene triphenylphosphorane (15.4 g, 44.1 mmol), and toluene (150 mL), stir and heat at reflux. After 22 hours, cool to ambient temperature and concentrate under vacuum. Add ether and filter off the triphenylphosphine oxide precipitate and concentrate the ether filtrate. Flash chromatograph with 0% to 10% ethyl acetate/hexanes to yield the titled compound (6.71 g, 99%) as a clear oil. TLC Rf=0.58 in 8:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (m, 1H), 6.81-6.79 (m, 3H), 6.73 (s, 1H), 5.14 (s, 1H), 4.07 (q, J=14.4, 7.2, 2H), 3.80 (s, 3H), 3.80-3.69 (m, 1H), 3.39-3.36 (m, 1H), 2.20-2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.96-1.87 (m, 3H), 1.65-1.54 (m, 2H), 1.2 (t, J=1.2, 8, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=C(C3C=CC(NC(NC4C=C(C(F)(F)F)C=CC=4F)=O)=CC=3)C([C:47](NCC(F)(F)F)=[O:48])=C(Br)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10]([CH:47]=[O:48])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Reactant: Nc1ncnn2c(Br)c(C(=O)NCC(F)(F)F)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O

Procedure:
The procedure used for the preparation of Intermediate AU was used to prepare the title compound by substituting Intermediate AV (N-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea) for Intermediate AT (4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide). The title compound was obtained as isolated and was used without further purification. MS [M+H]+=503; LCMS RT=3.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][O:37][CH2:38][CH2:39][N:34]2[CH2:33][C@@H:32]([CH2:40]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][O:37][CH2:38][CH2:39][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC[C@@H]1CN2CCOC[C@H]2CO1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CN2CCOC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-yl]methanol (prepared as described in PCT Int. Appl. 2004006846) following General Procedure J.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2C=[CH:25][CH:24]=[CH:23][C:20]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:29]([O:32]CC)(=[O:31])[CH3:30]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:20]=[CH:23][CH:24]=[CH:25][C:30]=2[C:29]([OH:32])=[O:31])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:15])[CH3:16])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2cc(Nc3ccccc3C#N)c(Cl)cn2)n(C(C)C)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccccc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (80 g, 218 mmol) was dissolved in 1,4-dioxane (1.5 L) and 1 M NaOH (1500 mL, 1500 mmol) was added. The suspension was refluxed overnight. After cooling to RT, ethyl acetate (1 L) was added and layers were separated. The water layer was washed with 1 L of ethyl acetate. Both organic layers were combined and backwashed with 0.1 M NaOH (1 L) until no product was observed in organic. The organics were then discarded. Combined aqueous were then washed with 1 L of ethyl acetate. The water layer was then acidified with acetic acid (very slowly to ph ˜7). The solid was filtered and 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (67 g, 165 mmol, 76% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 2.11 (s, 3 H) 4.41 (quin, J=6.57 Hz, 1 H) 5.96 (s, 1 H) 6.83 (s, 1 H) 7.09 (ddd, J=8.02, 5.12, 3.03 Hz, 1 H) 7.40 (1 H) 7.52-7.61 (m, 2 H) 7.91-8.16 (m, 2 H) 8.55 (s, 1 H) 10.17 (brs, 1 H) 13.64 (brs, 1 H); HPLC Rt=2.35 min, MS (ESI): [M+H]+=386.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[C:21]([NH2:22])=[N:27][C:28]([NH2:30])=[N:29]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2C#N)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3nc(N)nc(N)c23)CC1
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
In a reaction vessel, 4-(2-cyano-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (613.7 mg; 2 mmol) and guanidine carbonate (360.6 mg; 2 mmol) were suspended in 2 mL DMA. The reaction mixture was heated to 145° C. for 22 hours. The mixture was cooled to room temperature and 4 mL of water was added and stirred for 15 minutes. The solid was collected by vacuum filtration and washed with water and ethyl acetate and dried under vacuum to yield 278.4 mg (40% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCOC1CCCCO1)OCC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.03 ml, 20 mmol) and the obtained residue was purified by Bach silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.59 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (5.46 g) in THF (100 mL) was added CDT (6.14 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50° C. After stirring at 50° C. for 1 h, the mixture was cooled to room temperature. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (5.04 g) and DIPEA (9.02 mL) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.05 g).
Reaction SMILES: COC1C=CC(C(O[C:10]2[C:15]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:14][C:13]([O:27]C)=[CH:12][C:11]=2[Br:29])=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(C)=CC=1>O>[Br:29][C:11]1[C:10]2[O:26][C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:16][C:15]=2[CH:14]=[C:13]([OH:27])[CH:12]=1
Reactant: COc1ccc(C(=O)Nc2cc(OC)cc(Br)c2OC(=O)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A suspension of 2-bromo-4-methoxy-6-[(4-methoxybenzoyl)amino]phenyl 4-methoxybenzoate (42.0 g, 86.4 mmol), p-toluenesulfonic acid monohydrate (32.8 g, 172.8 mmol) and anhydrous p-xylene (800 mL) was refluxed for 1 h with continuous water removal (Dean-Stark Trap). The initial suspension turned into a brown solution at refluxing temperature. The mixture was cooled to room temperature and washed with NaOH (2N). The organic layer was dried over MgSO4. Evaporation and crystallization from acetone/ethyl ether gave an off-white solid (23.5 g, 82% yield, m.p. 139–141° C.); MS m/e 334 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH:25]=[O:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[CH3:27][Mg]Br>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH:25]([OH:26])[CH3:27])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(C=O)c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)C1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Reaction time: 1 h

Procedure:
To a suspension of 75 mg (0.21 mmol) of aldehyde 3-1 in THF at −78° C. was added 80 μL (0.25 mmol) of methyl magnesium bromide solution (3M in Et2O). After stirring 1 h at that temperature, an additional 80 μL of the Grignard reagent was added and stirring was continued for 1 h more. The reaction was quenched with saturated NH4Cl, partitioned between brine and EtOAc, the organic phase washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 5-1 as a white solid. Data for 5-1: 1HNMR (500 MHz, CDCl3) δ 7.6 (m, 2H), 7.4-7.2 (m, 3H), 7.1-6.9 (m, 3H), 6.5 (s, 1H), 5.05 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.35 (m, 1H), 2.8 (s, 6H), 1.4 (m, 3H) ppm. HRMS (ES) calc'd M+H for C21H22F2N2O2: 373.1722. Found: 373.1713.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13](=[CH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S(C1C=C(C(C)(C)C)C(O)=CC=1C)C1C=C(C(C)(C)C)C([OH:31])=CC=1C.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)CCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][O:31]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Reactant: C=C(CS(=O)(=O)c1ccc(OC)cc1)C(=O)OCC
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CCOC(=O)C1(CS(=O)(=O)c2ccc(OC)cc2)CO1

Procedure:
To 2[(4-methoxybenzenesulfonyl)methyl]-acrylic acid, ethyl ester (38.4 g, 0.152 mol) in 200 mL of ethylene dichloride is added a small amount of the radical inhibitor 4,4′-thiobis-(6-t-butyl-3-methylphenol) [Ref: J.C.S. Chem. Commun., 1972, pp 64-65]. Technical grade m-chloroperoxybenzoic acid (MCPBA, 154 g) is added portionwise over about 45 minutes. The reaction becomes a heavy white slurry. Additional ethylene dichloride (150 mL) is introduced to facilitate stirring. The reaction is refluxed overnight, then cooled and concentrated under reduced pressure. The residue is mixed with ethyl acetate (250 mL) and aqueous sodium sulfite. Solid potassium bicarbonate is then slowly added. The phases are separated , and the aqueous phase is extracted with additional ethyl acetate (100 mL). The combined organic phases are washed with several portions of aqueous potassium bicarbonate, then saturated brine, and finally dried over magnesium sulfate. Filtration and evaporation provides the crude product as a pale yellow oil. Chromatography on silica gel, eluting with a gradient of 40% to 60% ethyl acetate in hexanes, affords the title compound. m.p. 77-79° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].Cl[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-chloro-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Off-white solid. MS (ESI): 330.1 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2.[Li]CCCC.CCCCCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[F:12][C:10]1[CH:11]=[C:2]([B:28]([OH:33])[OH:29])[CH:3]=[C:4]2[C:9]=1[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2
Reactant: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Bromo-9-fluoro-4,5-dihydro-1-methyl[1,2,4]triazolo[4,3-a]quinoline (1-5, 3.90 g, 13.8 mmol) was dissolved under nitrogen atmosphere in dry THF and cooled to −78° C. A 2.5 M n-BuLi solution in hexane (V=6.60 ml, 16.6 mmol) was added dropwise and stirred at −78° C. for 30 min. Triisopropyl borate (V=4.5 ml, 19.3 mmol) was added in one portion and the temperature raised to −50° C. for additional 30 min. The mixture was allowed to warm up to 0° C. and quenched with a 1M KHSO4 solution in order to reach pH 3. The solution was basified with a 2M NaOH solution and washed twice with ethyl acetate. The water layer was neutralized with conc. HCl and the precipitate was successively washed with water and ether and dried under reduced pressure to obtain the title compound as a white solid; MS (ESI): m/z=248.04 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:3]([O:5][Si](OCC)(C)C)=[O:4].C(O)C>>[CH3:1][C:2]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:3]([OH:5])=[O:4]
Reactant: C=CCC(C)(C)C(=O)O[Si](C)(C)OCC
Solvent: CCO
Product: C=CCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A 100-ml four-necked flask equipped with a Dimroth reflux condenser, stirrer and thermometer was purged with nitrogen. The flask was charged with 17.7 g (0.0768 mol) of ethoxydimethylsilyl 2,2-dimethyl-4-pentenoate and 14.2 g (0.307 mol) of ethanol. The contents were stirred at room temperature for one hour, then at 60-65° C. for 5 hours. The reaction mixture was vacuum distilled, collecting 9.2 g of a colorless clear fraction having a boiling point of 78-79° C./0.6 kPa. On NMR and GC/MS analysis, the liquid was identified to be the target compound, 2,2-dimethyl-4-pentenoic acid. The yield was 93.4%. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 11.9 (1H, br), 5.84-5.70 (1H, m), 5.11-5.08 (1H, m), 5.07-5.04 (1H, m), 2.30 (2H, dt, J=7.3 Hz, 1.1 Hz), 1.19 (6H, s) 13C-NMR (CDCl3, 75.6 MHz): δ (ppm) 184.6, 133.9, 118.2, 44.4, 42.2, 24.5 MS (EI): m/z 128 (M+), 113, 83, 55, 41
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C)c1C
Yield: 47.4 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml), and 2-methoxyphenyl isocyanate (116 mg) was then added to the solution. The mixture was allowed to react at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/acetone (211) to give 169 mg (yield 47%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccnn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cccnn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 47.2 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyridazin-3-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.35 g, 1.06 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.076 g, 3.2 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl and extracted with EtOAc (2×10 mL). The organic extracts were washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 90:10) to give [1-hydroxy-4-methyl-6-(pyridazin-3-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.15 g, 47%). 1H NMR (400 MHz, DMSO): δ 9.23 (s, 1H), 9.01 (dd, J=1.2, 4.4 Hz, 1H), 7.79-7.76 (m, 1H), 7.47 (dd, J=1.2, 9.2 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 5.54 (dd, J=2.4 Hz, 1H), 3.10 (dd, J=2.4, 15.6 Hz, 1H), 2.32 (s, 3H), 2.19-2.12 (m, 1H). MS (ESI) m/z=299 [M−H]−.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:43])[CH2:40][O:41][CH3:42]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39](=[O:43])[CH2:40][O:41][CH3:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: COCC(=O)N(C)OC
Product: COCC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N,2-dimethoxy-N-methylacetamide.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:6]=1[C:7]#[N:8]>C1COCC1.CCOC(C)=O>[Cl:16][C:9]1[C:6]([C:7]#[N:8])=[C:5]([NH:3][CH2:1][CH3:2])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of ethylamine in THF (2 M, 13.8 mL, 27.6 mmol) was added slowly to a solution of 2,6-dichloro-3-nitrobenzonitrile (3.0 g, 13.8 mmol) in THF (30 mL) at −5° C. After 1.5 h, the solution was diluted with EtOAc (150 mL) and washed with 0.5 N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (8:1:1 hexanes/CHCl3/EtOAc) gave 2.57 g (82%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (br s, 1H), 8.30 (d, 1H, J=8.8 Hz), 6.78 (d, 1H, J=8.4 Hz), 3.89-3.97 (m, 2H), 1.41 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C9H8N3O2Cl, 226, 228; found 226, 228.