Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:6][N:7]=[C:8]([C:18]1[C:19]([Cl:25])=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])=O)C.[S:26](Cl)(Cl)=O>>[Br:24][C:22]1[CH:23]=[C:18]([C:8]2[N:7]=[N:6][S:26][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:19]([Cl:25])=[N:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)NN=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Product: Clc1cccc(-c2snnc2-c2cc(Br)cnc2Cl)c1Cl
Reaction time: 3.5 h
Yield: 50 %

Procedure:
A solution of ethyl-2-(1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethylidene)hydrazinecarboxylate (3.03 mmol) was stirred in thionyl chloride (20 mL). The solution was heated from 0° C. to RT and stirred for 3.5 hours. The solvent was evaporated to give a yellow oil which was adsorbed onto Celite™ and purified by silica gel chromatography (5-40% EtOAc/hexanes) to give 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridine as a yellow solid (640 mg, 50% yield over 2 steps).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:55]>CC(C)=O.O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29][C:30]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:55]
Reactant: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h

Procedure:
2.628 g of the product of Example 34 in resin form were dissolved at room temperature in 5.2 ml of acetone and 10.4 ml of a molar solution of sodium bicarbonate in water were added thereto all at once. The mixture stood at 20° C. for 1 hour and was then vacuum filtered. The recovered precipitate was rinsed twice with 2 ml of a 1-1 water-acetone mixture and with 2 ml of distilled water and was dried at 40° C. under reduced pressure to obtain 1.612 g of the syn isomer of raw sodium 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [O:1]([C:8]([P:19](=[O:26])([O:23]CC)[O:20]CC)([P:11](=[O:18])([O:15]CC)[O:12]CC)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C[Si](C)(C)Br>[O:1]([C:8]([P:19](=[O:20])([OH:23])[OH:26])([P:11](=[O:12])([OH:15])[OH:18])[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(CC)(Oc1ccccc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: CCC(Oc1ccccc1)(P(=O)(O)O)P(=O)(O)O
Reaction time: 8 h

Procedure:
A solution of tetraethyl (1-phenoxypropylidene)-bisphosphonate (2.1 g) in trimethyl bromosilane (8 ml) was kept at room temperature overnight, followed by evaporation in vacuo. The residue was stirred overnight in absolute ethanol. Evaporation in vacuo gave the desired compound.
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([C:22]([O:24]CC)=O)=[N:19][CH:18]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC(OCC(C)C)=O.Cl.[CH3:36][O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40]>C1COCC1.CCN(CC)CC>[CH3:42][CH:41]([CH3:43])[CH:39]([NH:40][C:22]([C:20]1[S:21][C:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)=[CH:18][N:19]=1)=[O:24])[C:38]([O:37][CH3:36])=[O:44]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
N-methyl morpholine (1.01 ml) was added to a solution of 5-(4-nitrophenyl)thiazole-2-carboxylic acid (Intermediate 2, step B, 2.3 g) in THF (72 ml). The reaction mixture was stirred for 10 minutes at RT, cooled to −20° C. Isobutyl chloroformate (1.19 ml) was added and the mixture was stirred for 15-20 minutes at −20 to −30° C. This was followed by the addition of L-valine methyl ester hydrochloride (2.15 g) previously neutralized with Et3N (1.8 ml). The reaction mixture was stirred at −20 to −30° C. for 5 minutes and was then allowed to gradually warm to RT. The solvent was removed under reduced pressure and the crude material was chromatographed on silica gel in 15:85 EtOAc:CHCl3 to get pale yellow colored solid which was crystallized in EtOAc/Pet ether to yield 2.25 g (67%) of the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 8.95 (d, 1H), 8.7 (s, 1H), 8.34 (d, 2H), 8.09 (d, 2H), 4.33 (m, 1H), 3.68 (s, 3H), 2.27 (m, 1H), 0.95 (t, 6H); MS (ES+): m/z 364 (M+1).
Reaction SMILES: [CH2:1]1[CH2:6][NH:5][CH2:4][C:3]2[C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:2]1=2.C(N(CC)CC)C.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:34][CH:33]2[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]2)[CH2:28]1>>[CH:33]12[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]1)[CH2:28][N:27]([CH2:26][CH2:25][N:5]1[CH2:6][CH2:1][C:2]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:7](=[O:15])[C:3]=3[CH2:4]1)[CH2:34]2
Reactant: O=c1oc2ccccc2c2c1CNCC2
Reactant: ClCCN1CC2CCCC(C2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c2c1CN(CCN1CC3CCCC(C3)C1)CC2
Reaction time: 72 h
Yield: 35.5 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (0.8 g, 0.004 moles), triethylamine (1.3 ml, 0.009 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (1.0 g, 0.0045 moles). The reflux time is 72 hours. The crude product is triturated in 10% aqueous potassium carbonate, filtered off, rinsed with water, and dried to give the product (0.5 g), mp 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([Cl:1])=[N:3][CH:4]=[N:5]2
Reactant: Cc1ccn2ncnc(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnn2ccc(CBr)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A mixture of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (2.0 g, 11.93 mmol, WO 03/042172) and AKIN (195 mg, 1.19 mmol) in CCl4 (80 mL) under N2 was heated to 100° C. for 5 min, NBS (2.55 g, 14.3 mmol) was added. The reaction mixture was stirred for 10 min, then cooled to rt, filtered. The CCl4 layer was washed with dilute NaHCO3 aqueous solution, dried (MgSO4), filtered and concentrated to give the desired product (2.70 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Reactant: Cc1ccc(F)cc1O
Product: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1cc(F)ccc1C)n2-c1ccccc1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 32, step 6, (100 mg, 212 μmol) and 5-fluoro-2-methylphenol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[Na+].CN([CH:29]=[O:30])C>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:29]=[O:30])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Phosphorous oxychloride (185.0 mg, 1.20 mmol) was added to DMF (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. To this solution was added 6-fluoro-5-(4-methoxy-phenyl)-1H-indole (147.0 mg, 0.61 mmol) in DMF (2 mL) and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was cooled to room temperature, treated with 1 N aqueous NaOH (3 mL) and heated to 100° C. for 1 minute. The reaction mixture was cooled to room temperature and filtered. The collected solids were air dried to give the title compound (106 mg, 65% yield). MS (ES+) 270.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][CH:27]1[CH:31]=[CH:30][CH:29]([CH3:32])[NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH:29]([CH3:32])[CH:30]=[CH:31][CH:27]1[CH3:26])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1C=CC(C)N1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2C(C)C=CC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2,5-dimethyl-2,5-dihydropyrrole, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.52 minutes; C23H22Cl2N4O2 (457.36); mass spectrum: (M−H)−=456/458/460 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7](=[O:12])[NH:8][CH:9]([CH3:11])[CH3:10])[N:6]=1.[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)=[O:22])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([NH:20][C:21](=[O:22])[NH:23][C:24]1[N:25]=[CH:26][C:27]([C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7](=[O:12])[NH:8][CH:9]([CH3:11])[CH3:10])[N:6]=2)=[CH:28][CH:29]=1)[CH3:19]
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)NC(C)C
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)NC(C)C)c(C(=O)OCC)s2)cn1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
In a 10 mL of microwave vial, ethyl 2-chloro-4-isopropylcarbamoyl-thiazole-5-carboxylate (Intermediate 28, 1.1 g, 3.97 mmol), N-ethyl-N′-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-urea (Intermediate 1, 1.15 g, 3.97 mmol), cesium carbonate (1.29 g, 3.97 mmol), Tetrakis (triphenylphosphino) palladium (0) (0.458 g, 0.397 mmol) in 15 mL of 4:1 dioxane:H2O was degassed for 30 min, then heated to 100° C. for 30 min. The reaction mixture was diluted with ethyl acetate (25 mL), then washed with water (10 mL). The organic layer was dried, then concentrated under reduced pressure to yield crude a residue which was purified by column chromatography over silica gel to afford 0.195 g (17.72%) of the title compound as solid. MS (APCI): 406 (M+H−) for C18H23N5O4S; NMR: 1.13 (t, 3H), δ 1.16 (d, 6H), 1.28 (t, 3H), δ 3.2 (q, 2H), 4.04 (m, 1H), 4.29 (q, 2H), 7.63 (d, 1H), 7.70 (br s, 1H), 8.27 (dd, 1H), δ 8.45 (d, 1H), 8.83 (d, 1H), 9.56 (s, 1H).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: O=C(O)C(F)(F)C(F)(F)Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(F)(F)C(F)(F)Br

Procedure:
To a solution of 7.0 g (31 mmol) of 3-bromo-2,2,3,3-tetrafluoropropionic acid in 40 ml of ethanol was added 1.0 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 8 hours and then distilled under ordinary pressure to give an ethanolic solution of ethyl 3-bromo-2,2,3,3-tetrafluoropropionate. Ammonia gas was blown into the solution, which was left at room temperature overnight and then concentrated under reduced pressure to give 5.6 g of 3-bromo-2,2,3,3-tetrafluoropropionamide as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN1CCCCC1)CO2

Procedure:
Preparation according to Example 3 using [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), piperidine (1 ml) and ACN (3 ml). Yield: 0.3 g, 94%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 227° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α]=−65° (MeOH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH:12]1[C:17](=O)[NH:16][CH2:15][CH2:14][N:13]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.[OH-].[Na+]>C1COCC1>[CH2:19]([N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH:12]1[CH2:11][CH2:10][OH:9])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC1C(=O)NCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CNCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Lithium aluminum hydride (4.6 grams, 120 mmol) was slowly added to a solution of (1-benzyl-3-oxo-piperazin-2-yl)-acetic acid ethyl ester (11 g, 40 mmol) in THF (150 mL) at 0° C. The mixture was allowed to stir for 18 h while warming to RT. The mixture was placed in and ice/water bath and additional lithium aluminum hydride (3.0 g, 80 mmol) was added. The mixture was allowed to stir for 20 h while warming to RT. 1 N NaOH was added until all of the LAH was consumed resulting in a white solid. The mixture was filtered through a pad of celite, washing with additional THF (50 mL). The filtrate was concentrated in vacuo to give 8 g (90%) of the title compound as an oil: APCI MS m/z 221.2 (M+1).
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[F:12][C:13]([F:30])([F:29])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26](O)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.ON1C2C=CC=CC=2N=N1.CN.C(O)C>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:1][NH:2][C:26]([C:21]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:30])([F:29])[F:12])=[CH:15][CH:16]=2)=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
At 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7.2 g, 37.57 mmol) was added to a solution of 4′-(trifluoromethyl)-2-biphenylcarboxylic acid (10.0 g, 37.57 mmol) and 1-hydroxybenzotriazole ( 5.1 g, 37.57 mmol) in DMF (50 ml) and DCM (20 ml). The reaction mixture was stirred for 20 min at 0° C. An 8.3 M solution of methylamine in ethanol (94 ml, 751 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (100 ml). The aqueous phase was extracted with ethyl acetate (3×70 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (2:1) as eluent, to give 8.50 g of 4′-(trifluoromethyl)biphenyl-2-carboxylic acid methylamide.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11](C4C=CN=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[F:28][CH:29]([F:48])[O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[O:46][CH3:47]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:28])[F:48])=[C:32]([O:46][CH3:47])[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1OC(F)F
Yield: 39.8 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2-(4-(difluoromethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123.3 mg, 0.411 mmol) as a starting material to afford 50.0 mg (39.8%) of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(difluoromethoxy)-3-methoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.68 (dd, J=1.8, 2.4 Hz, 1H), 7.55 (s, 1H), 7.21 (d, J=8.4 Hz, 1H). 7.07 (t, J=75 Hz, 1H), 5.58-5.50 (m, 1H), 3.92 (s, 3H), 3.72-3.65 (m, 1H), 3.39 (t, J=9.5 Hz, 1H), 3.20 (dd, J=4.8, 6.9 Hz, 1H), 2.88-2.81 (m, 1H), 2.34-2.28 (m, 2H), 1.41 (d, J=5.7 Hz, 3H), 1.11-0.99 (m, 4H), LCMS-ESI+ (m/z): [M+H]+ calcd for C23H24F2N4O4:458.18; found 459.09.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1O.[H-].[Na+].CS(Cl)(=O)=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CN(C)[C@@H]1CCCC[C@H]1O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCCCC1NCc1ccccc1
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of trans-2-dimethylaminocyclohexanol (58 g.; 0.405 mole) in 80 ml. of THF was added during 10 minutes to a suspension of NaH (17.05 g.; 0.405 mole of 57% dispersion in mineral oil) in 240 ml. of THF and the mixture was refluxed for 3 hours. It was cooled to 10°, and methanesulfonyl chloride (46.39 g.; 0.405 mole) was added dropwise during 30 minutes keeping the temperature below 15°. Benzylamine (86.79 g.; 0.81 mole) was then added during 5 minutes, the solvent was evaporated and heating continued at 95° for 16 hours. NaOH (500 ml. of 20% solution) was added and the mixture heated at 95° for 1 hour, cooled and extracted with ether (5×100 ml.). The ether solution was extracted with 10% HCl (6×100 ml.) and backwashed once with ether (discard). The acid extract was cooled, basified with 20% NaOH and extracted well with ether. The ether solution was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated. Distillation at 0.4 mm gave 61 g. (65% yield) of N,N-dimethyl-N'-benzyl-1,2-cyclohexanediamine, b.p. 112°. It was identical by tlc to the sample prepared by the reaction of benzylamine with trans-2-chloro-dimethylaminocyclohexane.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14])([CH3:3])[CH3:2].[C:15](Cl)(Cl)=[O:16]>>[N:14]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[C:15]=[O:16]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(C(C)C)cc1OC
Product: COc1cc(N=C=O)c(C(C)C)cc1OC

Procedure:
1-Isocyanato-2-isopropyl-4,5-dimethoxy-benzene was prepared by reaction of 2-isopropyl-4,5-dimethoxy-phenylamine with phosgene following the procedure of step 2 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][N:24]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])[C:25]([O:27][CH2:28][CH:29]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:35]3[C:30]2=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:53])([CH3:52])[C:19](=[O:51])[N:20]2[CH3:50])=[CH:15][CH:14]=1.Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:22]([CH2:23][N:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[C:21]3[C:16]([NH:17][C:18]([CH3:52])([CH3:53])[C:19](=[O:51])[N:20]3[CH3:50])=[CH:15][CH:14]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CN(C(=O)OCC2c4ccccc4-c4ccccc42)c2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
7-(2-Methoxy-4-methoxymethoxyphenyl)-8-[N-(2-methoxyphenyl)-N-(9-fluorenylmethoxycarbonyl)aminomethyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 12-1, 137 mg, 0.192 mmol) was dissolved in 1,4-dioxane (1 mL) and 4N hydrochloride/1,4-dioxane solution (144 μL, 0.576 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (71.6 mg) as a colorless solid. (Yield 56%)
Reaction SMILES: [CH3:1][O:2][Si:3]([O:12][CH3:13])([O:10][CH3:11])[CH2:4][SiH:5]([O:8][CH3:9])[O:6][CH3:7].C(Cl)(Cl)(Cl)[Cl:15]>[Pd](Cl)Cl>[Cl:15][Si:5]([O:8][CH3:9])([O:6][CH3:7])[CH2:4][Si:3]([O:12][CH3:13])([O:10][CH3:11])[O:2][CH3:1]
Reactant: CO[SiH](C[Si](OC)(OC)OC)OC
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl[Pd]Cl
Product: CO[Si](Cl)(C[Si](OC)(OC)OC)OC
Reaction time: 4 h

Procedure:
A solution of 7.27 mmol (1.29 g) of palladium (II) dichloride [PdCl2 (II)] in 30 ml of carbon tetrachloride is placed in a flask, and then 0.106 moles (24 g) of 1,1,1,3,3-pentamethoxy-1,3-disilapropane (98%, Korea Institute of Science and Technology (KIST)) is slowly added thereto at 0° C. The reaction is allowed to proceed at this temperature for 4 hours. The reaction mixture is filtered through celite to obtain 3-chloro-1,1,1,3,3-pentamethoxy-1,3-disilapropane.