Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH2:45][C:46]([F:49])([F:48])[F:47])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(CN(CC(F)(F)F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (92 mg) in DMF (0.89 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (77 μL) and potassium carbonate (74 mg) at 0° C., and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to 0° C., potassium carbonate (246 mg) was added, and the mixture was stirred at 80° C. for 2 days. The reaction mixture was cooled to 0° C., 2,2,2-trifluoroethyl trifluoromethanesulfonate (256 μL) was added, and the mixture was further stirred at 80° C. for 3 days. The mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was directly used for the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CNCC2
Yield: 94 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-phenethylpiperazin-1-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (180 mg, 0.368 mmol) was deprotected and converted to the dihydrochloride salt according to Example 2 (step g) to provide the title compound (134 mg, 94%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.59 (d, J=8.3 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.40-7.33 (m, 4H), 7.32-7.28 (m, 1H), 7.08-7.07 (dd, J=8.3, 1.7 Hz, 1H), 4.45 (s, 2H), 4.28-4.16 (m, 2H), 4.16-4.01 (m, 2H), 3.95-3.76 (m, 2H), 3.72 (s, 3H), 3.63-3.55 (m, 4H), 3.27-3.16 (m, 2H), 3.13-3.08 (m, 2H); ESI MS m/z 389 [M+H]+; HPLC (Method B)>99% (AUC), tR=10.1 min.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li]C.Cl[Si:11]1([CH3:15])[CH2:14][CH2:13][CH2:12]1>CCOCC>[C:1]([Si:11]1([CH3:15])[CH2:14][CH2:13][CH2:12]1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCC
Reactant: C[Si]1(Cl)CCC1
Agent: [Li]C
Solvent: CCOCC
Product: CCCCCC#C[Si]1(C)CCC1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1-heptyne (1.31 mL, d=0.7238, 0.960 g, 10.0 mmol) in Et2O (10 mL) was added a solution of MeLi (9.43 mL, 1.06 M in Et2O, 1.0 equiv) at −78° C. After being stirred for 3 h, 1-chloro-1-methylsilacyclobutane (1.16 mL, 1.0 equiv) was added dropwise to the reaction solution at the same temperature, which was then stirred for another 5 h. The reaction mixture was quenched with H2O (10 mL) and then was extracted with pentane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by column chromatography (SiO2, pentane) and Kugelrohr distillation to afford 1.66 g (92%) of 1-(1heptynyl)-1-methylsilacyclobutane as colorless oil
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[CH3:28][O:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][CH:30]([O:29][CH3:28])[CH2:31][CH2:32]1
Reactant: COC1CCNCC1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Product: COC1CCN(CCOc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-methoxy-piperidine.
Reaction SMILES: [CH:1]([N:4]=[CH:5][CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:1]([NH:4][CH2:5][CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(=CC=NC(C)C)c1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(=CCNC(C)C)c1ccccc1-c1ccccc1
Reaction time: 5 h

Procedure:
A solution of 2.63 g of 1-isopropylimino-3-p-biphenylyl-2-butene (obtainable from 3-p-biphenylyl-2-butenal and isopropylamine) in 20 ml of absolute ether is added dropwise to a solution of 0.6 g of LiAlH4 in 20 ml of absolute ether. The mixture is then boiled for 5 hours, water is added carefully and the mixture is worked up in the customary manner to give 1-isopropylamino-3-p-biphenylyl-2-butene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](O)=[O:18])(=O)C>CC(C)=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10])[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[OH:14]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O
Yield: 100.1 %

Procedure:
2,6-Dichloro-4-aminophenol (0.37 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. While mixing, an acetone solution (10 ml.) of the acid chloride prepared from acetylsalicylic acid (0.38 g.) was added by drops. After the reaction was completed, the solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and then was washed with water then with 1N-hydrochloric acid. After evaporating off the ethyl acetate under reduced pressure the resulting residue was dissolved in a mixture of methanol and 2N-sodium hydroxide (10 ml. each). The solution was agitated for several hours then acidified with 2N-hydrochloric acid to precipitate the product. By recrystallization in acetone-water, white needle-like crystals of 3',5'-dichloro-2,4'-dihydroxybenzanilide (0.62 g.) were obtained. The yield was 78% and the melting point was 217-219° C.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[F:33][CH:34]([F:65])[CH2:35][O:36][C:37]1[CH:64]=[CH:63][C:40]([C:41]([NH:43]/[C:44](/[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[CH:45]\[C:46]2[CH:51]=[CH:50][C:49]([O:52][C:53]([F:56])([F:55])[F:54])=[CH:48][CH:47]=2)=[O:42])=[CH:39][CH:38]=1>>[F:65][CH:34]([F:33])[CH2:35][O:36][C:37]1[CH:64]=[CH:63][C:40]([C:41]([NH:43][CH:44]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][C:53]([F:54])([F:55])[F:56])=[CH:48][CH:47]=2)[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(NCCO)/C(=C/c1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCC(F)F)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCC(F)F)cc1
Yield: 73.4 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(2,2-difluoroethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide (190 mg) to give 140 mg of the title compound (white powder).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(Cl)Cl.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=1>[Cl-].[Na+].O>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[C:31]([O:36][CH3:37])[CH:30]=1
Reactant: C1=COCCC1
Reactant: COc1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
3,4-Dihydro-2H-pyran (2.0 mL) and pyridinium p-toluenesulfonate (370 mg) were added to chloroform solution (30 mL) of 4-bromo-2-methoxyphenol (3.0 g) and stirred at room temperature for 12 hours. Saturated brine was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-200; ethyl acetate:hexane=1:19) to provide the title compound (3.64 g, 86%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]([CH2:2][C:3]([N:5]3[CH2:9][C:8](=[O:10])[N:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=4[CH3:18])[CH2:6]3)=[O:4])[C:25](=[O:27])[O:26][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2c(=O)oc3cc(Cl)ccc32)CC1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76) (28.6 mg, 1 equiv), 6-Chloro-3H-benzooxazol-2-one (16.9 mg, 1 equiv) and potassium carbonate (27 mg, 2 equiv) in DMF (2 ml) was stirred at 60° C. overnight, diluted with ethyl acetate, washed with water, purified with HPLC to give 6-chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (77): LCMS observed for (M+H)+: 421.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>O1CCCC1>[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: NCc1ccccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1cc2ncnc(NCc3ccccc3N)c2cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
4-Chloro-7-ethylamino-6-nitroquinazoline (5.00 g, 19.8 mmol), triethylamine (8.3 ml, 60.9 mmol), and 2-aminobenzylamine (2.9 g, 23.8 mmol) were stirred at room temperature overnight in tetrahydrofuran. After the reaction was completed, the solution was concentrated under reduced pressure, and the resulting solids were washed with methanol to give the title compound (5.23 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O.C(#N)C>[N+:12]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:10])([O-:14])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
5-Methoxy-2-nitrobenzoic acid (A) (25.0 kg, 1.0 eq.), 2-amino-5-chloropyridine (B) (16.3 kg, 1.0 eq.), and acetonitrile (87.5 kg, 3.5 parts) were charged to a 380 L GLMS reactor. The reaction mixture was adjusted to 22° C. (19-25° C.) and anhydrous pyridine (30.0 kg, 3.0 eq.) was added. The pump and lines were rinsed forward with acetonitrile (22.5 kg, 0.9 parts), and the reactor contents were adjusted to a temperature of 19-22° C. Phosphorous oxychloride (23.3 kg, 1.20 eq.) was charged to the contents of the reactor via a metering pump, while maintaining a temperature of 25° C. (22-28° C.). The metering pump and lines were rinsed forward with acetonitrile (12.5 kg, 0.5 parts), while keeping the temperature at 25° C. (22-28° C.). The reaction mixture normally turned from a slurry to a clear solution after the addition of about ⅓ of the POCl3. At the end of the addition, it became turbid. After complete addition, the reaction mixture was agitated at 25° C. (22-28° C.) for ca. 1 hr, at which time HPLC analysis confirmed reaction completion. The solution was cooled to 15° C. (12-18° C.) and drinking water (156.3 kg, 6.25 parts) was charged slowly while keeping reaction temperature of between 12 and 30° C. The reaction mixture was then adjusted to 22° C. (19-25° C.) and agitated for ca. 5 hrs until exotherm ceased. Formation of a slurry was visually confirmed and the contents of the reactor were filtered onto a pressure nutsche fitted with a filter cloth. The reactor, pump, and lines were washed forward onto the pressure nutsche with two portions of drinking water (62.5 kg, 2.5 parts each). The filtrate had a pH value of 7. The product (41.8 kg) was dried under vacuum with a maximum temperature of water bath (to heat dryer jacket) of 50° C. After ca. 12 hrs, in-process LOD analysis indicated a solvent content of 0.72%. The dry product (C) was discharged (34.4 kg) with 88.2% yield and 99.1% purity by HPLC.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]#[N:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>O1CCCC1>[CH3:16][S:17]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[C:4]#[N:5])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C=CC(C#N)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C=CC(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
2-hydroxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile (1.8 g; 9 mmol) is dissolved in 15 ml of anhydrous tetrahydrofuran, and cooled to 0° C. Methanesulfonyl chloride (0.93 ml, 0.012 mol) is added at once, followed by triethylamine (2 ml, 0.015 mol) dropwise over 20 min, keeping the temperature of the mixture below 5° C. The mixture is then stirred at 2° C. for 1 h 15 min, and poured into 200 ml of iced water. The suspension is extracted with ethyl acetate, the organic extract is washed neutral with water, then with brine, and dried over magnesium sulfate. Rotary evaporation of the solvent and recrystallization from 80 ml of ethanol yields 2-methylsulfonyloxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile (1.02 g; 41%) as light yellow hair-like crystals, mp 147-152° C. (dec). 1H-NMR reveals the presence of only one isomer.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([Cl:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (146 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-8, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C@H:2]([C@H:7]([OH:11])[CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH3:6])=[O:4].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[CH2:8]([C@H:7]1[O:11][C@@H:2]1[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH3:10]
Reactant: CCC[C@@H](O)[C@@H](Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CCC[C@H]1O[C@@H]1C(=O)OC
Temperature: 15 °C
Reaction time: 14 h
Yield: 104 %

Procedure:
Methyl (2R,3R)-2-chloro-3-hydroxyhexanoate (0.9 g, 5 mmol), ethanol (10 ml) and potassium carbonate (2.1 g, 15 mmol) were mixed, and the mixture was stirred at 15° C. for 14 hours. Methyl tert-butyl ether (20 ml) was added. The mixture was washed with water (10 ml) three times. The organic layer was concentrated under reduced pressure to obtain the title compound (0.75 g, yield: 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:32][OH:33])[CH2:27]1)(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[OH:33][CH2:32][C@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@@H]3CO)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 83 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-hydroxymethyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried afford intermediate N-Boc protected product as a colorless solid (102 mg, 86%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4,-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 83% overall). 1H NMR (D2O) 2.17 (s, 3H), 3.26-3.46 (m, 3H), 3.60-3.80 (m, 3H), 4.00-4.04 (m, 1H), 4.48 (dd, J=12.7, 5.3, 1H), 4.60 (obs dd, J=13.2, 3.5, 1H), 7.46 (d, J=4.3, 1H), 7.82 (d, J=4.0, 1H). 19F NMR −63.5. LC/MS 3.89 min, [M+1]+ 376.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:34])=[CH:17][C:18]([F:33])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:41][N:42]([CH3:46])[C:43]([NH2:45])=[O:44].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C.CCOC(C)=O.O>[F:32][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:19]2[C:18]([F:33])=[CH:17][C:16]([CH3:34])=[C:15]([C:7]3[C:8](=[O:14])[N:9]([CH2:12][CH3:13])[C:10]4[C:5]([CH:6]=3)=[CH:4][N:3]=[C:2]([NH:45][C:43](=[O:44])[N:42]([CH3:46])[CH3:41])[CH:11]=4)[CH:20]=2)[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2C)cc2cnc(NC(=O)N(C)C)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3,5-difluorophenyl)urea (287 mg, 0.589 mmol), Cs2CO3 (576 mg, 1.768 mmol), N,N-dimethylurea (260 mg, 2.95 mmol) and Xantphos (102 mg, 0.177 mmol) in dioxane (5 mL) was sparged with Ar, treated with Pd2(dba)3 (81 mg, 0.088 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with water, EtOAc and DMF and the solids removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and stirred overnight. The resulting solid was collected via filtration and dried to afford 3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (18 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.17 (s, 1H), 8.65 (m, 2H), 8.01 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.20-7.11 (m, 3H), 6.78 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 539.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.I[CH2:18][CH2:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)[CH2:13][CH:12]=1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2c(ccn2-c2ccncc2)c1
Reactant: ICCC1Cc2ccccc2C1
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
A mixture of 5-chloro-1-(pyridin-4-yl)-1H-indole 26a (4.0 g), 2-(2-iodoethyl)indane 24a (4.8 g), and methyl isobutyl ketone (100 ml) was boiled under reflux for 20 h. The mixture was cooled, and a crystalline compound collected by filtration (6.5 g). Compound corresponding to 5.5 g was suspended in methanol (100 ml), and NaBH4 (1.5 g) was added in parts of 0.5 g. The resulting mixture was stirred at room temperature for I h, and the solvent was removed in vacuo. Conventional work up with ethyl acetate and water followed by purification on silica gel eluted with ethyl acetate-heptane (1:1) gave the crude product, which was crystallized (ethyl acetate) to give the title compound (1.1 g, 27%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH:13][CH:14]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:19]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])[C@H:17]([OH:18])[C@H:15]1[OH:16]>>[OH:13][CH:14]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:19]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])[C@H:17]([OH:18])[C@H:15]1[OH:16].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
U.S. Pat. No. 6,057,135 discloses a process for manufacturing D-tagatose, wherein a lactose permeate is hydrolysed to obtain a lactose hydrolysate comprising D-galactose and glucose. The hydrolysate is fermented to convert the glucose to ethanol which is subsequently removed and the remaining solution of D-galactose is subjected to enzymatic isomerisation with an L-arabinose isomerase to obtain D-tagatose. The L-arabinose isomerase preparations used are crude biomass extracts of Lactobacillus pentosus, Bacillus amyloliquefaciens or Arthrobacter spp