Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH2:5]=O.[CH2:7]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[CH3:2][N:3]([CH2:5][C:15]1[N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:4]
Reactant: c1ccc(Cn2cccc2)cc1
Reactant: C=O
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)Cc1cccn1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 8.2 g. (0.1 mole) dimethylamine hydrochloride in 8 ml. formalin is added dropwise to 17.12 g. (0.1 mole) of 1-benzylpyrrole. The mixture is stirred at room temperature until solution occurs (about 4 hours). The solution is poured into 10% sodium hydroxide solution and then extracted into ether three times. The combined organic fractions are washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent evaporated in vacuo. The product, 2-dimethylaminomethyl-1-benzylpyrrole, is distilled at reduced pressure, b.p. 73° C., 0.025 mm. Hg.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH:6]=[CH:5][CH2:4][N:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[NH2:9][C@H:8]1[CH2:7][CH:6]=[CH:5][CH2:4][N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]1=[O:1].[F:26][C:25]([F:28])([F:27])[C:23]([O-:29])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CCN(c2ccccc2)C1=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC=CCN(c2ccccc2)C1=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a round bottom flask was added (S,Z)-tert-butyl 2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (85 mg, 0.28 mmol), DCM (1 mL) and TFA (1 mL). The reaction mixture was stirred at rt for 2 hr. The reaction mixture was concentrated and dried under high vacuum for 1 h to afford (S,Z)-3-amino-1-phenyl-3,4-dihydro-1H-azepin-2(7H)-one, trifluoroacetate (87 mg, 0.28 mmol, 98% yield) as an oil. Anal. Calcd. for C12H14N2O m/z 202.2. found: 203.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.[NH2:25][CH:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:27]#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:26]([C:27]#[N:28])[NH:25][C:15]([C:14]2[C:13]([CH3:18])=[N:12][N:11]3[C:6]([O:5][CH2:4][C:3]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=4[F:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=23)=[O:17])=[CH:34][CH:33]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: N#CC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC(C#N)c3ccc(Cl)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged in a 96-well deep well multititre plate. A solution of 17 mg (0.10 mmol) of rac-amino(4-chlorophenyl)acetonitrile in 0.4 ml of DMF and a solution of 45.6 mg (0.12 mol) of HATU in 0.4 ml of DMF were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Then the mixture was filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.7 mg (1.5% of theory) were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH:20][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:15]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCNc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a solution of 3-Fluoro-4-nitrobenzonitrile (1.0 g, 6.0 mmol) in DMA (5 mL) were added Beta-Alanine ethyl ester HCl (1.4 g, 9.03 mmol) and DIPEA (1.6 mL, 9.03 mmol). The reaction mixture was stirred at room temperature for 16 h (the reaction was completed; the reaction mixture turned to orange from yellow in color). The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford 1.53 g (96%) of the desired product as yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=O)[CH3:13].[CH2:25]([O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[CH3:26]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:33])=[C:30]([CH3:31])[NH:32][C:17]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:24])[CH3:13]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
7.5 g of 3-nitrobenzaldehyde, 9.4 g of γ-acetoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol are heated under reflux for 20 hours, the mixture is cooled and the precipitate is filtered off.
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].Cl.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33]N>C(O)(=O)C>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:33]([C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: NNc1ccc(F)cc1F
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccc(F)cc2F)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.0162 mol) was dissolved in Acetic acid (50 mL). 2,4-Difluorophenylhydrazine hydrochloride (3.52 g, 0.0195 mol) was added and the reaction was stirred at 95° C. overnight. The acetic acid was removed in vacuo. The crude was loaded as a solid onto silica gel and purified by flash chromatography (4-10% methanol in methylene chloride) to afford 3.662 g 8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as an orange solid. MS (ESI+) 458.0/460.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[CH3:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36]>>[CH3:33][C:34]([CH3:38])([CH3:37])[C:35]#[C:36][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1[C@@]21CCOC(N)=N1

Procedure:
The titled compound was synthesized by steps analogous to those described in method A2 above, but using intermediate 18B, 2-fluoropyridin-3-ylboronic acid and 3,3-dimethylbut-1-yne. MS m/z=443.0 [M+H]+. Calculated for C26H23FN4O2: 442.48
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:42]=[O:43])C>C1COCC1.C1CCCCC1>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:8]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([F:13])=[C:11]([CH:12]=1)[CH:42]=[O:43])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)c(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: -78 °C

Procedure:
A solution of 55.0 g of 4-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxy)-fluorobenzene described in example 3.1 in 120 ml THF was cooled to −78° C. Within 30 min 97 ml of an 1.3 M solution of sec-butyllithium in cyclohexane was added dropwise. After stirring at −78° C. for an hour, 9.7 DMF in 18.3 ml THF was added within 20 min. The mixture was stirred at −78° C. for 1 hr, then warmed to r.t. within 90 min and quenched with 300 ml ice-cold water. The product was isolated by extraction with Et2O to yield 60.6 g 5-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-benzaldehyde as yellow liquid.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C1(C)C(C)=CC=CC=1>[CH2:19]([O:14][C:13](=[O:15])[C:12]1[C:8](=[CH:7][C:3](=[C:2]([CH:16]=1)[C:1]([O:18][CH2:9][CH2:8][CH2:7][CH2:3][CH2:2][CH2:16][CH2:12][CH3:13])=[O:17])[C:4]([O:6][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:5])[C:9]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Reactant: CCCCCCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: CCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCC)c(C(=O)OCCCCCCCC)cc1C(=O)OCCCCCCCC
Yield: 209 %

Procedure:
To a 2-liter four necked flask equipped with Dean Stark, 218 g of anhydrous pyromellitic acid, 650 g of n-octanol, 0.2 g of titanium tetraisopropoxide and 300 ml of xylene were added and reacted with agitation at 160 degrees C. for 4 hours under nitrogen stream while distilling water. Subsequently, washing by saturated saline and washing by 0.1 N aqueous sodium hydroxide were respectively conducted three times, followed by being dried by anhydrous magnesium sulfate. After magnesium sulfate was filtered, unreacted alcohol was distilled under diminished pressure to obtain 630 g of pyromellitic acid tetraoctyl ester as a residue. The obtained compound, regarded as Comparative 1-3, was similarly measured with respect to the properties.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[F:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:51][CH2:52]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2ccc(CN3CCNCC3)c(F)c2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC3)c(F)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
A 25 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with triphosgene (55.0 mg, 0.190 mmol, 0.35 equiv), 1,1,1,3,3,3-hexafluoropropan-2-ol (133 mg, 0.790 mmol, 1.51 equiv) and dichloromethane (3 mL). N,N-diisopropylethylamine (204 mg, 1.58 mmol, 3.00 equiv) was added dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. 1-[[2-Fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine (150 mg, 0.530 mmol, 1.00 equiv) in dichloromethane (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 3 h at 0° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (320 mg) was purified by preparative HPLC using the following gradient conditions: 30% CH3CN/70% Phase A increasing to 70% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 30% CH3CN over 0.1 min, and holding at 30% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 102 mg (40% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate as a white solid. 1H NMR 400 MHz (CDCl3) δ 7.73-7.76 (m, 2H), 7.65-7.69 (m, 1H), 7.47-7.53 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 5.74-5.80 (m, 1H), 3.60-3.69 (m, 6H), 2.65 (s, 3H), 2.49 (br, 4H). LCMS (ESI, m/z): 480 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][C:12]([N:39]3[CH2:40][CH2:41][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH2:37][CH2:38]3)=[O:14])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)CC1CCC2(CC1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1CCC2(CC1)OCCO2)N1CCN(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
An ice-cold solution of 1,4-dioxaspiro[4,5]-decane-8-acetic acid (20.0 g) (Example G) and triethylamine (20.9 ml) in 100 ml of dichloromethane is treated dropwise with a solution of isobutyl chloroformate (19.4 ml) in 100 ml of dichloromethane under nitrogen. The resulting solution is stirred at 0° C. for 10 minutes and a solution of 1-(2-pyridyl)-piperazine (32.59 g) in 100 ml of dichloromethane is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then at room temperature for one hour. After washing with 1 L of a saturated solution of sodium bicarbonate, the organic phase is dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by MPLC (silica; ethyl acetate) to give 25.50 g of the title compound as a colorless solid; mp 113°-116° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH2:32])[CH3:22].C(O)(=O)C.[Na]>CCCCCC.C(OCC)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)=[O:33])[CH3:22]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc(F)ccc1N[C@H]1CC[C@H]2CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]2C1
Yield: 21.1 %

Procedure:
Following the procedures from Example 1A, and using ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg, 1.9 mmol), 2-amino-5-fluoro-benzoic acid ethyl ester (183 mg, 1.0 mmol), glacial acetic acid (0.36 mL, 6.0 mmol), and sodium triacethoxyborohydride (590 mg, 2.8 mmol), flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 95 mg (22% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CS(C)=O>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC[C@H]1CCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (8 mL) was added DIEA (650 mg, 5.03 mmol), and (2R)-2-(methoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75° C. Then the reaction was quenched by the addition of water (50 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (650 mg, 81%).
Reaction SMILES: [Br:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:15]=[C:14]([O:16][CH:17]([F:19])[F:18])[C:12]([NH2:13])=[CH:11][CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5].[Br:22]N1C(=O)CCC1=O.O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][C:11]1[CH:10]=[C:9]([C:3]([F:8])([C:4]([F:7])([F:6])[F:5])[C:2]([Br:1])([F:20])[F:21])[CH:15]=[C:14]([O:16][CH:17]([F:18])[F:19])[C:12]=1[NH2:13]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
4-(1-Bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)aniline (810 mg) was dissolved in acetic acid, added with N-bromosuccinimide (390 mg), and stirred at 70° C. for 3 hours. Water was added to the reaction solution and extraction was carried out twice using ethyl acetate. The organic phases were combined and neutralized with sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoroprop-2-yl)-6-(difluoromethoxy)aniline (730 mg, 75%).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[CH:46]=[N:47][N:48]([C:50]([CH3:55])([CH3:54])[CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[CH:46]=[N:47][N:48]([C:50]([CH3:55])([CH2:51][CH2:52][OH:53])[CH3:54])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CC(C)(CCO)n1cc(Br)cn1
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(C(C)(C)CCO)c2)ccc1N
Yield: 42.8 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 649 mg, 2.34 mmol) and 3-(4-bromo-pyrazol-1-yl)-3-methyl-butan-1-ol (Compound 50D, 600 mg, 2.57 mmol) to afford 304 mg of the title compound (43%). 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=0.5 Hz, 1H), 8.01 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 3.40 (t, J=7.2 Hz, 2H), 2.94 (s, 3H), 2.17 (t, J=7.3 Hz, 2H), 1.66 (s, 6H). MS (ESI): m/z=304.26 [M+H]+. UPLC: tR=0.77 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])([O-:3])=[O:2].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH2:22]([O:21][CH:20]=[C:15]([C:16](=[O:18])[CH3:17])[C:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])[CH3:23]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
A mixture of 1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione (11.0 g), triethyl orthoformate (11.3 g) and acetic anhydride (12.3 g) was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness. Toluene (50 ml) was added and the mixture was evaporated to dryness to give 2-ethoxymethylene-1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione as a crude brown oil which was not further purified.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)(O)=O.S(N)([NH2:17])(=O)=O.S(Cl)(Cl)=O.O>S1(CCCC1)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)#[N:17]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 135 °C
Reaction time: 0.25 h

Procedure:
5-Carboxyphthalid (50 g, 0.28 mole) and sulfamide (31 g, 0.32 mole) were suspended in sulfolane (150 mL). Thionylchloride (41 g, 0.34 mole) was added and the temperature was raised to 130-140° C. for 2 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool to 90° C. and water (150 mL) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (250 mL). The title compound was crystallised from acetic acid.Yield: 34.5 g, 77%. DSC onset: 203° C. Purity: 98.5% (hplc, peak area). 1H NMR (DMSO-d6, 500 MHz): 5.48 (2H, s), 8.03 (2H, s), 8.22 (1H, s). 13C NMR (DMSO-d6, 125 MHz): 70.0, 116.1, 188.0, 126.0, 127.5, 129.0, 132.8, 147.7, 169.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(C(C)=O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc(C(C)O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-(1-(2,2,2-trifluoroethoxy)-ethyl)pyrimidin-4-yl)ethanone (90 mg, 0.20 mmol) was dissolved in ethanol (5 mL). Sodium borohydride (30.3 mg, 0.80 mmol) was added in portions. The mixture was stirred at rt for 10 min. Acetone (2 mL) was added and the mixture was stirred for 20 min. The mixture was filtered, the volatiles were removed in vacuum, and the residue was purified by preparative HPLC to yield the title compound consisting of four stereoisomers, 64 mg (71%).