Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1.[N+:14]([C:17]1[NH:21][N:20]=[CH:19][CH:18]=1)([O-:16])=[O:15].[Br-].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][C:8]1([C:5]2[O:4][C:3]([CH2:2][N:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[N:21]3)=[N:7][CH:6]=2)[O:12][CH2:11][CH2:10][O:9]1
Reactant: O=[N+]([O-])c1ccn[nH]1
Reactant: CC1(c2cnc(CCl)o2)OCCO1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(c2cnc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl]-methanol (35 mg, 0.19 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with Et3N (0.03 mL, 0.25 mmol) followed by DMAP (2.3 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at rt for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole as a yellow oil. A solution of this crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole (38 mg, 0.19 mmol) in acetone (1.0 mL) was treated with 5-nitro-1H-pyrazole (21 mg, 0.19 mmol) and TBA bromide (12 mg, 0.04 mmol) followed by K2CO3 (77 mg, 0.56 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:6 hept-EA)=0.15. LC-MS-conditions 02: tR=0.83 min; [M+H]+=281.05.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccncc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)cc23)CC1
Yield: 69.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol) pyridine-4-carboxylic acid, 7.0 mg of the title compound were recovered.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][NH:26][NH2:27].CC(O)C>O>[F:24][C:20]1[CH:21]=[C:22]2[N:26]([CH3:25])[N:27]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:17]2=[N:18][CH:19]=1
Reactant: CNN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (300 mg), methylhydrazine (212 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and then at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was dissolved in EtOH (20 mL) and 10% Pd—C (50% wet, 98 mg) was added. The mixture was stirred for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (125 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:64]1(=[O:70])[CH2:69][CH2:68][CH2:67][CH:66]=[CH:65]1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:66]2[CH2:67][CH2:68][CH2:69][C:64](=[O:70])[CH2:65]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1C=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Yield: 23 %

Procedure:
[4-(Benzyloxy)phenyl]boronic acid (2 g, 8.77 mmol) was dissolved in dioxane/water (50 mL/5 mL) and Rh(acac)(C2H4)2 (68 mg, 0.26 mmol) and racemic BINAP (164 mg, 0.26 mmol) were added. The mixture was degassed 3 times and put under a nitrogen atmosphere. Cyclohexenone (1.02 mL, 10.52 mmol) was added to the yellow solution and the mixture heated at reflux overnight. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution (50 mL) added, then extracted with EtOAc (2×100 mL). The organic extracts were washed with water (100 mL) and dried. Volatile material was removed by evaporation and purification by chromatography gave the title compound (565 mg, 23%) as a solid; 1H NMR δ1.65-1.69 (1H, m), 1.78-1.93 (2H, m), 1.99-2.04 (1H, m), 2.22-2.35 (2H, m), 2.39-2.43 (1H, m), 2.65 (1H, m), 2.90-2.96 (1H, m), 5.08 (2H, s), 6.96 (2H, d), 7.20 (2H, d), 7.31-7.45 (5H, m); MS m/e MH+ 281.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH2:11].C([Sn](CCCC)(CCCC)[CH2:18][O:19][CH3:20])CCC.CN1C(=O)CCC1.[F-].[K+]>C1C=CC([P]([Pd]([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)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:18][O:19][CH3:20])=[N:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCc1ccc(C(=O)OC)c(N)n1
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 63.2 %

Procedure:
A mixture of 2-amino-6-chloro-nicotinic acid methyl ester (1.4 g) described in Manufacturing Example 11-2, tributyl-methoxymethyl-tin (3.1 g) described in Manufacturing Example 11-3-1, tetrakis(triphenylphosphine)palladium(0) (440 mg), and NMP (20 mL) was stirred for 3.5 hours at 130° C. The reaction solution was allowed to cool, an aqueous potassium fluoride solution and ethyl acetate were added thereto under ice cooling, after which the reaction mixture was filtered through Celite. The organic layer was washed with saturated brine, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (0.93 g).
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3].[OH:24]O.[OH-].[Na+]>CO.O.[Cl-].[Na+].O>[O:24]1[C@:9]23[C@:4]([CH2:1][C:2]#[CH:3])([CH2:5][CH2:6][C:7](=[O:23])[CH:8]12)[C@@H:21]1[C@H:12]([C@H:13]2[C@@:17]([CH2:19][CH2:20]1)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3
Reactant: OO
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CC[C@]12CCC(=O)C3O[C@@]31CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 650 mg of 10-(2-propynyl)estr-4-ene-3,17-dione in 5 ml of methanol at 15° C. is added 0.6 ml of 30% hydrogen peroxide. A solution of 46 mg of sodium hydroxide in 0.4 ml of water is then added dropwise. After 1 hour at 15° C., the solution is stirred for 2 hours at 25° C. before it is poured into brine. The aqueous mixture is then extracted with ether and the ether solution is dried and concentrated. The residual material obtained is recrystallized from methanol to give 4,5β-epoxy-10-(2-propynyl)estrane-3,17-dione. This epoxide is added to 5 ml of acetic acid containing 0.1 ml of concentrated sulfuric acid and the mixture is stirred at 25° C. for 4 hours before it is poured into ice. The solid which forms is separated by filtration and recrystallized from ethyl acetate to give 4-hydroxy-10-(2-propynyl)estr-4-ene-3,17-dione. This compound has the following structural formula ##STR15##
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:14]1[CH:38]=[CH:37][CH:36]=[CH:35][C:15]=1[O:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]1[N:26]([CH3:34])[C:27](OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:48]>>[ClH:48].[CH2:7]([C:14]1[CH:38]=[CH:37][CH:36]=[CH:35][C:15]=1[O:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]1[N:26]([CH3:34])[CH3:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(Cl)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (401 mg, 10.6 mmol), cis-1-(2-benzylphenoxy)-2-(N-methyl-N-tert-butoxycarbonylamino)indane (453 mg, 1.06 mmol) and tetrahydrofuran (50 ml). After a reaction time of 3 h the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a pale green oil (331 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 222°-225° C. (from methanol-diethyl ether).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].Cl[CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[CH2:25]1[CH2:35][CH2:34][N:33]2C(=NC[CH2:31][CH2:32]2)CC1.O>CN(C)C=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:18][CH2:17][CH2:16][CH2:15][CH2:14][N:12]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]([CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:32]2[CH:31]=[CH:25][CH:35]=[CH:34][N:33]=2)[C:10]1=[O:11]
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: ClCCCCSc1ccccn1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CCCCSc2ccccn2)c(=O)n1CCCCSc1ccccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
To a solution of 1.62 g (10 mmol) of benzoylene urea and 2.02 g (10 mmol) of 2-(4-chlorobutylthio)pyridine in 50 ml of dimethylformamide, 1.65 ml (11 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=2:1 to 1:2). First, 221 mg of the desired product was obtained (4.6% yield, yellow oil), and then, 292 mg of 3-[4-(2-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione was obtained (8.9% yield, white crystals).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:3].[CH3:11][N:12]([C:21]([S:23][CH3:24])=[NH:22])[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl>[CH3:11][N:12]([C:21](=[N:22][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[S:23][CH3:24])[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Reactant: COC(=O)CCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 920.2 %

Procedure:
Methyl 4-(chloroformyl)butyrate (31.2 g) was added dropwise during 1 h at 20° to a stirred solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (3.60 g) and triethylamine (20.0 g) in dichloromethane (100 ml). The pale yellow suspension was stirred at 20° C. for 16 h. A further portion of methyl 4-(chloroformyl)butyrate (6.2 g) and triethylamine (4.0 g) was added and stirring continued for a further 1 h. Water (100 ml) was added, the organic layer separated and washed successively with saturated aqueous sodium bicarbonate and water, dried, and evaporated to give a brown solid (53.6 g). This solid was recrystallised from ether to give the title compound (30.9 g) as a pale yellow solid m.p. 69°-70°.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1>>[CH:15]1([CH2:18][C@H:19]([NH:23][C:2]2[O:3][C:4]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[C:20]([NH:34][CH2:33][CH2:32][NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:22])[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]1
Reactant: NCCNc1ccc(F)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Fc1ccc2nc(Cl)oc2c1
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2ccc(F)cc2o1

Procedure:
The title compound was prepared from 2-chloro-6-fluorobenzoxazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.18(m, 2H), 7.30(dd, 1H, J=2.4 Hz, J=8.6 Hz), 7.11(dd, 1H, J=4.8 Hz, J=8.4 Hz), 6.89(m, 1H), 6.84(m, 2H), 6.51(m, 2H), 4.28 (m, 1H), 3.15(m, 2H), 2.95(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28F2N4O2 (M+H+)443.22. found 443.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.CS(O[C@H:17]([C@@H:19]1[CH2:23][C:22](=[O:24])[N:21]([C@@H:25]([C:27]2[CH:32]=[CH:31][C:30](OC)=[CH:29][CH:28]=2)[CH3:26])[CH2:20]1)[CH3:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:17]([C@H:19]2[CH2:20][N:21]([C@@H:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH3:26])[C:22](=[O:24])[CH2:23]2)[CH3:18])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Oc1cc(Br)cn2nccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@H]([C@@H](C)Oc2cc(Br)cn3nccc23)CC1=O
Temperature: 90 °C

Procedure:
To a solution of 6-bromopyrazolo[1,5-a]pyridin-4-ol (125 mg, 0.587 mmol) in DMF (4 mL) was added (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (220 mg, 0.645 mmol) and Cs2CO3 (239 mg, 0.733 mmol) and the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was diluted with EtOAc and water, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried, filtered, and concentrated. The residue was purified by flash chromatography to afford (R)-4-((R)-1-(6-bromopyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 6.01.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.13 g, 0.29 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.083 g, 0.38 mmol) according to the general procedure VI. Obtained as an off-white solid (0.07 g, 52%). MS (ISP) 461.3 [(M+H)+]; mp 179° C.
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[O:11]=[C:12]1[O:18][C@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[C:15]([OH:16])=[C:13]1[OH:14].[CH2:23]1[O:31][CH:24]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[OH:31][CH2:23][CH:24]([O:16][C:15]1[C@@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[O:18][C:12](=[O:11])[C:13]=1[OH:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: c1ccc(C2CO2)cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=C1O[C@H]([C@@H](O)CO)C(OC(CO)c2ccccc2)=C1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Under an argon atmosphere, 4 ml of 1,1,1,3,3,3-hexafluoro isopropanol and 10 ml of acetonitrile were added to L-ascorbic acid (1.00 g), and further, styrene oxide (1.37 g) was added. The mixture was heated up to 70° C. and stirred for 48 hours, then, concentrated under reduced pressure, and 2.73 g of the resultant residue was subjected to silica gel column chromatography. Thereafter, it was eluted with chloroform/methanol/water(volume ratio:20/3/0.3) to obtain two elution fractions (first eluted fraction: 225 mg, later eluted fraction: 228 mg). Based on the measurement results of high resolution mass analysis, infrared absorption spectrum, 1H-NMR, 13C-NMR and specific optical rotation on the resultant elution fractions, it was confirmed that these are two 3-O-(2-hydroxy-1-phenylethyl) ascorbic acids which are in mutual stereoisomerism and both of them are represented by the following structural formula.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:16]=1[CH2:17][N:18]1[CH2:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]1=[O:26]>C(Cl)Cl.O>[CH3:1][S:2]([O:25][CH2:24][C:21]1([CH3:23])[CH2:20][C:19](=[O:26])[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:15]=2[O:14][CH3:13])[CH2:22]1)(=[O:4])=[O:3]
Reactant: COc1ccc(CN2CC(C)(CO)CC2=O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2CC(C)(COS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (305 mg, 2.65 mmol) and triethylamine (540 mg, 5.35 mmol) were added to a solution of 1-(2,4-dimethoxybenzyl)-4-(hydroxymethyl)-4-methylpyrrolidin-2-one (500 mg, 1.75 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 16 hours and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give [1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidin-3-yl]methyl methanesulfonate. MS ESI calc'd. for C16H24NO6S [M+H]+ 358. found 358. 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J=8.4 Hz, 1H), 6.46-6.44 (m, 2H), 4.41 (s, 2H), 4.02-3.96 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.22 (d, J=6.4 Hz, 1H), 2.99-2.95 (m, 4H), 2.41 (d, J=16.8 Hz, 1H), 2.24 (d, J=16.8 Hz, 1H), 1.19 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1.CC#N>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 134, 152 mg, 0.34 mmol) in CH2Cl2 (15 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooled by the ice bath, and was then allowed to warm to r.t. then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3 and then brine. The organic solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude product (100 mg) as a beige solid after trituration with diethyl ether. CH3CN (˜3 mL) was then added to the crude product and the resulting slurry was stirred at 50° C. for 4 h. After cooling to r.t. the suspended solid was collected by filtration, washed with CH3CN and dried at 45° C. overnight to give the title compound (72 mg, 42%) as a yellow solid; 1H NMR: 1.68-1.81 (3H, m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H, m), 3.00-3.05 (2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H, s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd), 6.48-6.56 (2H, m), 6.96 (1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z: ES+ MH+ 503.67.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of methyl 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate (1.75 g) in methanol (15 ml) is added potassium hydroxide (1.0 g) in water (10 ml). The resulting mixture is stirred at RT until a clear solution is obtained (about 20 min). Most of the methanol is removed, and the aqueous solution is acidified with dilute HCl and extracted with ether. The combined ether extracts are dried and concentrated to dryness to give 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionic acid.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].C[N:7](C=O)C.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1.Cl>O.C(Cl)(Cl)Cl>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([S:1]([NH2:7])(=[O:3])=[O:2])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2c(c1)OCO2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: NS(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (0.18 mol; 24.3 g) is added dropwise to cooled DMF (0.18 mol; 13.14 g) at a rate to maintain <10° C. The reaction complex is stirred at <10° C. for 30 min. 1,3-Benzodioxole is added dropwise over a period of 10 min. The reaction is then warmed to 80° C. and held for 10 min, and finally warmed to 110° C. and held for 10 min. During heating, the reaction turns brown and HCl evolution is observed. The reaction is cooled to room temperature and left overnight under nitrogen. Next, the reaction is poured onto ice (˜150 g), chloroform (70 mL) and water (70 mL). The organic layer is collected and dripped into concentrated ammonium hydroxide (70 mL), yielding a precipitate, which is collected by filtration, washed with water and dried in vacuo at 40° C. to produce 10.28 g of benzo(1,3)dioxole-5-sulfonamide.