Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][CH2:33][CH2:34][C:35]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]=[C:37]([O:45][CH:46]2[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]2)[CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[OH:32][CH2:33][CH2:34][C:35]1[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]=[C:37]([O:45][CH:46]2[CH2:51][CH2:50][CH:49]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:48][CH2:47]2)[CH:36]=1
Reactant: O=C1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCC(Oc6cc(CCO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.9 g, 3.9 mmol), and 4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexanone (1.3 g, 4.3 mmol), in dry tetrahydrofuran (36 mL) were stirred for 15 min under nitrogen. Sodium triacetoxyborohydride (1.7 g, 8.2 mmol) was then added. The mixture was stirred at 20° C. for 16 hours. HPLC and LCMS analysis showed clean conversion to the trans and cis products (M+H 698; 1:1 ratio). The reaction was quenched with water, concentrated, stirred with 20% KHCO3 and extracted with ethyl acetate, dried (Na2SO4), filtered, and evaporated to give 2.8 g. The isomeric products were separated by prep LCMS using a Waters instrument and a 30 mm×100 mm Xbridge C18 column; 60 mL/min; 55% CH3CN—H2O (0.1% NH4OH); 0.5 min; 4.5 gradient to 72%; 24 runs; retention time trans isomer, 4.6 min; cis isomer, 5.4 min. The isolated cis isomer contained <1% residual trans isomer. Yield 1.00 g cis isomer, 37% yield. 1H NMR (500 MHz, CDCl3; also COSY, HSQC, and HMBC): δ8.83 (s, 1H); 8.40 (s, 1H); 8.28 (s, 1H); 7.40 (m, 1H); 6.80 (m, 1H); 6.67 (s, 1H); 5.64 (s, 2H, SEM); 5.17 (m, 111, OCH); 4.01 (t, 211, OCH2); 3.74 (s, 2H, NCH); 3.59 (m, 2H, NCH); 3.55 (t, 2H, SEM); 3.38 (s, 2H, CH2CN); 2.95 (t, 211, CH2); 2.30 (m, 1H, NCH); 2.15 (m, 2H); 1.84 (m, 2H); 1.50 (m, 2H); 1.30 (m, 2H); 0.90 (t, 2H, SEM); −0.92 (s, 9H, SEM).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][NH:5]2.Cl[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cnccn1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Solvent: ClCCl
Product: CN1C[C@@H]2C[C@H]1CN2c1cnccn1
Temperature: 80 °C

Procedure:
A solution of 2.1 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane prepared by the procedure of U. Jordis et al, Synthesis, 1990, 925, and 1.8 ml of 2-chloropyrazine in 8 ml of diazabicyclo[3.6.0]undecene-5 is heated to approximately 80° C. for 2 hours. The reaction solution is cooled, diluted with 100 ml of methylene chloride and washed with 30 ml of 5N aqueous sodium hydroxide. The organic layer is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride) to give 2.1 g of the desired product as a pale yellow oil:
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([OH:20])[C@@H:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:1]([O:4][CH2:5][C@@H:6]([O:20][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOC[C@H](C(=O)OC(C)(C)C)[C@H](O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C=CCOC[C@H](C(=O)OC(C)(C)C)[C@@H](COC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude material from Step 2 (0.090 g) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. To the cooled solution, was added 2,6-lutidine (0.10 mL, 0.90 mmol) followed by TBSOTf (0.10 mL, 0.4 mmol). The mixture was stirred at 0° C. for 2 h then diluted with H2O and sat'd NaHCO3. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the organic extracts dried (Na2SO4), filtered, and conc in vacuo. Purification on SiO2 (5-20% EtOAc/Hexanes) gave the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([CH2:14][CH2:15]C)[C:6]=1O.[OH:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24]C)=[O:22].[C:30](=[O:33])([O-])[O-].[K+].[K+]>>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=1[O:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:30]([OH:33])[C:6]=1[CH2:7][CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(C(C)=O)ccc(OCCBr)c1O
Agent: [K+]
Product: CCCc1c(OCCOc2ccccc2C(=O)OC)ccc(C(C)=O)c1O
Yield: 59 %

Procedure:
A mixture of 1.5 g of 1-[4-(2-bromoethoxy)-3-hydroxy-2-propylphenyl]ethanone, 0.76 g of ethyl 2-hydroxybenzoate and 1.05 g of potassium carbonate was allowed to react according to the procedure of Example 79 to give 1.1 g, m.p. 84°-87°, (59% yield) of 2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid methyl ester, the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)c(F)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.26 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=11.2 Hz), 6.98 (1H, d, J=8.0 Hz), 7.31-7.35 (1H, m), 7.38 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[CH:8]=1.[OH-].[Na+].Cl>CS(C)=O>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[CH:2]([CH3:5])[C:3]#[N:4]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Reactant: CC(Cl)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
A mixture of 2-chloropropionitrile (0.2 mole) and 1,3-dichloro-5-nitrobenzene (0.2 mole) in DMSO (50 ml) was added dropwise at RT to a solution of NaOH (1 mole) in DMSO (150 ml) while the temperature was kept below 30° C. The mixture was stirred at RT for 1 hour, then poured out on ice and acidified with HCl. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 70/30). The pure fractions were collected and the solvent was evaporated, yielding 19.5 g (40%) of (±)-2,6-dichloro-α-methyl-4-nitrobenzeneacetonitrile (intermediate 1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26].[ClH:40].Cl.C(OCC)(=O)C>>[ClH:40].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:16]=1)([CH3:26])[CH3:27]
Reactant: Cc1ccnc(Cn2cc(CNc3ccc(C(C)C)cc3)cn2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccnc(Cn2cc(CN(C(=O)Nc3c(C(C)C)cccc3C(C)C)c3ccc(C(C)C)cc3)cn2)c1

Procedure:
In the same manner as in Example 62, reaction and treatment were conducted using (4-isopropylphenyl)({1-[(4-methyl-2-pyridyl)methyl]pyrazol-4-yl}methyl)amine (0.42 g) and 2,6-diisopropylphenyl isocyanate (0.42 mL) as starting materials. Further, the obtained oil compound was converted to hydrochloride with 4N hydrochloric acid-ethyl acetate to give N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-({1-[(4-methyl-2-pyridyl)methyl]pyrazol-4-yl}methyl)urea hydrochloride (0.33 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CS(C)=O>[Cl:15][C:16]1[CH:23]=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 75 °C
Reaction time: 39 h
Yield: 100 %

Procedure:
To a suspension of D-allo-threonine (5.08 g, 42.7 mmol) and K2CO3 (10.32 g, 74.7 mmol) in DMSO (50 mL) was added 2-chloro-4-fluorobenzonitrile (5.53 g, 35.5 mmol) at room temperature. The reaction mixture was heated to 75° C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown solid (9.04 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.51 (d, J=8.8 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.83 (dd, J=2.4, 8.8 Hz, 1H), 6.31 (br d, J=7.6 Hz, 1H), 4.28-4.20 (m, 2H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[C:2]([F:1])=[CH:7][C:6]([OH:8])=[CH:5][C:4]=3[F:9])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(F)c(-c2ccc3cc(O)ccc3c2)c(F)c1
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol (510 mg, 1.86 mmol) and NCS (301 mg, 2.25 mmol) in THF (30 mL) according to Method C to yield 440 mg (77%) of yellowish solid: mp 213-214° C.;
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCCC>[Cu]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: COc1ccc(N)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reaction time: 4 h

Procedure:
A mixture of 80 g. 2-chlorobenzoic acid, 80 g. 4-anisidine, 80 g. potassium carbonate, 4 g. activated copper powder, and 800 ml. amyl alcohol was heated under reflux with efficient stirring for four hours. The amyl alcohol was removed by steam distillation and the remaining aqueous phase was filtered and made neutral by addition of 1:1 concentrated hydrochloric acid-water. The resulting solid (102 g.) was collected by filtration to give after recrystallization from isopropyl alcohol N-(4-methoxyphenyl)anthranilic acid; m.p. 183°-184°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[N+](C1C=CC([N:31]([CH:35]2[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]2)[C:32](=O)[O-:33])=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:32]([NH:31][CH:35]3[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]3)=[O:33])[CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1
Reactant: CC(C)(C)ON=C1CCC(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)CC1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)ON=C1CCC(NC(=O)N2CCn3c(Cl)c(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Temperature: 60 °C

Procedure:
A suspension of 0.27 (0.82 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide hydrochloride, 0.37 g (1.06 mmol) of 4-nitrophenyl[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-carbamate and 0.33 g (2.45 mmol) of sodium carbonate in 30 ml of acetonitrile is heated at 60° C. for 3 hours. After cooling, the mixture is poured into water and the product is extracted with dichloromethane. After drying over sodium sulfate and filtration, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of dichloromethane/ethyl acetate (60/40 to 20/80), to give 0.18 g of 6-chloro-7-(3-fluorophenyl)-N2-[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo-[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a yellowish powder, after evaporating the fractions down to a small volume of solvent, filtering off the crystallized product, washing with ethyl acetate and drying under reduced pressure.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])([CH2:13][CH3:14])[CH3:12].C(N(CC)CC)C.Cl>ClCCl>[CH:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH:16]=[O:17])([CH2:13][CH3:14])[CH3:12]
Reactant: C=CCC(CO)C(C)CC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(C=O)C(C)CC
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
Dimethyl sulfoxide (18.20 mL, 256.4 mmol) was added dropwise over 15 minutes to a dichloromethane (280 mL) solution of oxalic acid chloride (16.90 g, 133.1 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 25 minutes. Subsequently, a dichloromethane (75 mL) solution of 2-sec-butylpent-4-en-1-ol (12.20 g, 85.8 mmol) was added dropwise thereto over 30 minutes, and the mixture was stirred at −78° C. for 1 hour. Triethylamine (60.80 g, 600.8 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 2 N hydrochloric acid (310 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([OH:30])[C:26]([F:29])([F:28])[F:27].CC([O-])(C)C.[K+]>C1COCC1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:30][CH2:25][C:26]([F:29])([F:28])[F:27])/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
A mixture of the product from Example 75A (537 mg, 1.45 mmol), trifluoroethanol (87 μL, 2.18 mmol) and potassium 2-methylpropan-2-olate (2.18 mL, 2.18 mmol) in THF (10 mL) was stirred at room temperature for 3 hrs. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 258 mg (40%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.32 Hz, 3H) 1.36 (s, 9H) 1.40 (dd, J=7.63 Hz, 2H) 1.82 (m, 2H) 4.19 (t, J=7.32 Hz, 2H) 4.48 (q, J=8.54 Hz, 2H) 6.65 (s, 1H) 7.02 (d, J=8.54 Hz, 1H) 8.03 (d, J=2.75 Hz, 1H). MS (DCI/NH4+) m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].[NH2:19][C:20]1[N:25]=[C:24]([F:26])[CH:23]=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[N:21]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:19][C:20]1[N:25]=[C:24]([F:26])[CH:23]=[C:22]([O:27][C:28]([F:30])([F:31])[F:29])[N:21]=1)=[O:17])(=[O:13])=[O:14])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(F)cc(OC(F)(F)F)n1
Reaction time: 16 h
Yield: 21.5 %

Procedure:
5.9 g (20 mmol) of 2-(dimethylamino)sulfonylbenzenesulfonyl isocyanate were added to a solution of 4.0 g (20 mmol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine in 30 ml of methylene chloride at 25° C. Stirring was carried out for 16 hours at 25° C., and the product which separated out was filtered off under suction, washed with a little ether and dried at 50° C. under reduced pressure from a water pump. 2.1 g of the title compound (22% of theory) of melting point 167°-169° C. were obtained in this manner. Further product can be isolated from the mother liquor.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([S:10][C:11]#N)=[CH:8][N:9]=1)[C:2]([CH3:4])=[O:3].SC[C@H]([C@@H](CS)O)O.BrC[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CO.CN(C=O)C.O>[CH3:27][C:26]([O:25][C:23](=[O:24])[CH2:11][S:10][C:7]1[S:6][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[N:9][CH:8]=1)([CH3:29])[CH3:28]
Reactant: CC(=O)Nc1ncc(SC#N)s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ncc(SCC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in MeOH (360 mL) under argon was added dithiothreitol (9.26 g, 60 mmol) at rt. The mixture was stirred at rt for 2 h and it was concentrated to afford a reduced solid product. This solid product was dissolved in DMF (30 mL) and to this solution were added tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol). The mixture was stirred at rt for 2 h and water (200 mL) was added to the mixture. The precipitates were collected, washed with water and dried. The solid was dissolved in methylene chloride (100 mL) and MeOH (10 mL) and filtered through a silica gel pad. The filtrate solution was concentrated to afford the desired product (7.5 g, 87%) as a solid, mp 162-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Product: CS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 5-bromo-1H-indole-2,3-dione (Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381–4) and 4-methylsulfonylphenylhydrazine according to Procedure G: 1H NMR (DMSO-d6): δ 12.7 (s, 1H), 11.3 (s, 1H), 7.9 (d, 2H), 7.7–7.8 (m, 3H), 7.4 (dd, 1H), 6.9 (d, 1H), 3.2 (s, 3H); ESI-MS m/z 392 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4](C(Cl)(Cl)Cl)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([O:16][CH3:15])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h

Procedure:
25.3 g of 2-amino-4-cyclopropyl-6-trichloromethyl-1,3,5-triazine are added to a solution of 10.8 g of sodium methylate in 50 ml of methanol, and the mixture is stirred at 60° C. for 80 minutes. There are added 300 ml of water, and the formed suspension is filtered. The filter residue is suspended twice in 100 ml of acetyl acetate each time, and again filtered. The organic phases are collected, dried over magnesium sulfate and concentrated by evaporation to thus obtain an oil, which crystallises when stirred up in ether. The yield is 6.7 g of the title compound, m.p. 158°-159° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].COCCOCCOC.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>C(O)C.C(OCC)(=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:27][CH:26]=1
Reactant: Nc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccccc1-c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 2-bromoaniline (1.72 g, 10.0 mmol) in diglyme (30 mL) tetrakis(triphenylphosphine)-palladium(0) (0.13 g, 0.3 mmol) and 2.0 M aqueous sodium carbonate solution (15 mL, 30.0 mmol) were added. In a separate flask, 4-fluorophenylboronic acid (2.23 g 16.0 mmol) was dissolved in ethanol (8 mL) and the mixture containing 2-bromoaniline was added to this boronic acid solution. The obtained brown reaction mixture was heated at 80° C. for 6 hours, then cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and n-hexane:ethyl-acetate=2:1 as eluent to yield after recrystallization from ethanol 1.8 g (60%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH2:11]([Mg]Cl)[CH3:12].C[Mg]Cl.Cl>C1COCC1.C(CC(=O)C)(=O)C.[Fe+3].C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: CC[Mg]Cl
Agent: [Fe+3]
Agent: C[Mg]Cl
Agent: Cl
Solvent: CC(=O)CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc(Cl)ncc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-methoxypyrimidine (5 g) was dissolved in THF (50 ml), and while cooling, iron(III) acetylacetone (985 mg) and ethyl magnesium chloride (0.91 M: 36.9 ml) were then added to the solution. The obtained mixture was stirred at room temperature overnight. Thereafter, iron(III) acetylacetone (985 mg) and methyl magnesium chloride (0.91 M: 36.9 ml) were added to the reaction solution further twice. A 1 N hydrochloric acid aqueous solution was added to the reaction mixture, and liquid separation and extraction were then carried out with diethyl ether. The organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (1 g).