Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3](=[N:5][N+:6]([O-:8])=[O:7])[NH2:4].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:4][C:3](=[N:5][N+:6]([O-:8])=[O:7])[S:2][CH3:1])=[CH:14][N:13]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CSC(N)=N[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of 2-methyl-3-nitroisothiourea (15.0 g) in dimethylsulfoxide (100 ml) was gradually added sodium hydride (oil free 2.9 g) at 5° C., while being stirred for one hour. Thereafter, 2-chloro-5-chloromethyl pyridine (18.0 g) was added to the solution at a temperature in the range of from 5° to 10° C., followed by overnight stirring thereofat room temperature. After the dimethylsulfoxide in the solution was distilled off under reduced pressure, the resulting residue was purified on a chromatographic column (the eluent was a mixture of ethanol and chloroform), so as to obtain the desired 1-(2-chloro-5-pyridylmethyl)-2-methyl-3-nitroisothiourea (2.0 g) having a melting point in the range of from 141° to 143° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:8]1([C:7]2[CH:6]=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=[N:3][C:2]=2[N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1nnc(-c2ccccc2)cc1-c1ccccc1
Product: c1ccc(-c2cc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nn2)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 81.1 %

Procedure:
A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid. (320 mg, 0.81 mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979. Found 395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)cc1Cl
Yield: 90 %

Procedure:
2-Chloro-4,5-difluorobenzoic acid (19.2 g, 0.1 mol) was mixed with thionyl chloride (50 ml) and heated to reflux for 3 hours. The reaction mixture was evaporated to dryness, and the residue dissolved in methylene chloride. Solvent was removed in vacuo, and the procedure repeated once with methylene chloride and once with benzene. The material (19 g, 0.09 mol, 90% yield) was used without further purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[K].[F:7][C:8]1[C:9](=[S:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1>CN(C)C=O>[CH2:1]([S:15][C:9]1[C:8]([F:7])=[CH:13][NH:12][C:11](=[O:14])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
n-Butyl bromide (0.007 mol) was added to a solution of the potassium salt of 5-fluoro-4-thiouracil (0.006 mol) in dimethylformamide (30 ml) and the reaction mixture was stirred at room temperature for 3 days before evaporation at reduced pressure (1 mm Hg). The desired product was isolated from the residue by preparative paper chromatography (Whatman No. 3) using butanol:ethanol:ammonia:water (4:1:2:1); yield 20%, m.p. 113° C. (H2O). (Found: C, 47.20; H, 5.30. Calc. for C8H11FN2OS: C, 47.52; H, 5.48).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[1-(benzylmethylamino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 45.0 mg (75%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:15]2[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=23)=[O:19])[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Product: CN1CCC(NC(=O)c2cc(Cl)cc3oc(-c4ccccc4)nc23)CC1
Yield: 46 %

Procedure:
This material was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 4-amino-1-methylpiperidine using the method outlined in Step C of Example 7. This compound was obtained in 46% yield as a tan solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J=7.8 Hz, 1H), 8.23 (dd, J=6.6, 1.5 Hz, 2H), 8.18 (d, J=1.5 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.65-7.54 (m, 3H), 4.19-4.13 (m, 1H), 2.87 (d, J=1.5 Hz, 2H), 2.37 (s, 3H), 2.32-2.26 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.72 (m, 2H); MS (ESI) m/z 370 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[C:25]([C:10]2[N:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:4]=3)[N:9]=2)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(F)cc1F
Reactant: CSc1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1
Product: Fc1cnc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)c(F)c1

Procedure:
A solution of 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine and 3, 5-difluoro-2-tributylstannylpyridine were coupled together by the method of Example 36 to give 3-(3,5-difluoro-pyridin-2-yl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.34 (1H, m), 7.40-7.48 (2H, m), 7.56-7.60 (1H, m), 8.43-8.46 (1H, m), 8.54 (1H, dd, J 2.4, 6.6 Hz), 8.61 (2H, m), 9.78 (1H, s); m/z (ES+) 384.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].COC(C)(C)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:29])[NH:30][CH2:34][CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.2 %

Procedure:
To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[Mg].[CH2:12]([Si@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[CH:33][C:32](I)=[C:31]([F:36])[CH:30]=3)[CH2:25][CH2:24]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14]>C1COCC1>[CH2:12]([Si@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[CH:33][C:32]([C:2]4[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=4)=[C:31]([F:36])[CH:30]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:20]1)[CH2:13][CH3:14]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(I)c(F)c3)CC2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4cc(F)c(F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
21.1 g (0.1 mol) of 1-bromo-3,4,5-trifluorobenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 47.3 g (0.1 mol) of 4-(trans -4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl) -2-fluorophenyl iodide. After a conventional after treatment, purification was conducted by means of chromatography to obtain 37.7 g (yield 79.1%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,3',4',5'-tetrafluorobiphenyl was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1COCC1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([N:1]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:21])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Br)cc1C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1cc(Br)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a vial charged with 2-amino-5-bromobenzaldehyde (commercially available from Matrix Scientific, Columbia, S.C.) (0.500 g, 2.500 mmol) were added THF (4.17 mL), toluene (4.17 mL), TEA (0.871 mL, 6.25 mmol) and phthalic anhydride (0.849 mL, 8.75 mmol). The mixture was heated at 100° C. overnight. LC-MS indicated that the product was present as a component of a complex mixture. The resulting mixture was passed through a 10 g SCX-2 column with much solid sticking to the top of the column and some product eluting through indicating a solubility issue in MeOH. The solid and filtrate were dissolved in DCM:MeOH and the crude residue was adsorbed onto silica gel with drying under reduced pressure. The adsorbed material was purified with a 50 g SNAP column ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 5-bromo-2-(1,3-dioxoisoindolin-2-yl)benzaldehyde (0.290 g, 0.878 mmol, 35.1% yield) as a yellow solid. m/z (ESI) 330.0/332.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Li+].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[Br:1][C:2]1[C:3](/[CH:13]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)c(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL), and lithium methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100° C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added carefully (300 mL, exothermic). The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.9 mmol, 76% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:9][CH:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC1CCCC(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1CCCC(C)C1OC(=O)Cc1ccc(O)cc1
Yield: 51 %

Procedure:
A mixture of 2,6-dimethylcyclohexyl alcohol (11.4 g), 4-hydroxyphenylacetic acid (9.12 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) was refluxed with continuous water separation for 20 hours. The mixture was filtered and the filtrate was washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation in vacuo afforded 8.02 g of 2,6-dimethylcyclohexyl 4-hydroxyphenylacetate. That product has the structural formula: ##STR25##
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:11])[C:4]([CH3:10])=[CH:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH:15]=[O:16].Cl>C(#N)C.O>[OH:16][CH:15]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([OH:11])=[C:4]([CH3:10])[CH:5]=1)[CH:14]([O:17][CH3:18])[O:13][CH3:12]
Reactant: COC(C=O)OC
Reactant: Cc1ccc(C)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(OC)C(O)c1cc(C)c(O)cc1C
Yield: 81 %

Procedure:
A suspension of an aqueous solution of 5.2% sodium hydroxide (630 g), 2,5-xylenol (100 g), an aqueous solution of 60% glyoxal dimethyacetal (213 g) and water (200 g) was heated at 55° C. for 5 hours with stirring. The reaction mixture was cooled in an ice bath, and to the mixture were added acetonitrile (90 g) and 7.4% hydrochloric acid (380 g) successively. The precipitating crystals were filtered to give 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (150 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[CH3:37]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[CH3:37])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
Analogously to Example 4A, 1.50 g (4.13 mmol) of the compound from Example 3A are reacted with 704 mg (4.54 mmol) of 2-fluoro-5-nitrotoluene. This gives 570 mg (28% of theory) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:23][S:24]([O:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:21])[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:22])[F:1])=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(OC(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 386 (550 mg, 1.73 mmol) in DCM (20 mL) at 0° C. was added TEA (290 μL, 2.08 mmol) and MeSO2Cl (148 μL, 1.91 mmol) and stirring was continued for 1 h at 0° C. The mixture was diluted with EtOAc, washed sequentially with water, dilute HCl solution, aq. satd. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 685 mg (100%) of (R)-3-(tert-butoxycarbonylamino)-3-(4-(difluoromethoxy)phenyl)propyl methanesulfonate (388) containing some of the corresponding chloride.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1>COCCOC.O.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>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(F)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of sodium carbonate (5.79 g), tetrakis(triphenylphosphine)palladium(0) (0.631 g), 6-fluoropyridin-3-ylboronic acid (5 g) and 3-bromopyridin-2-amine (4.72 g) in DME (75 mL) and water (15 ml) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane, then. NH silica gel, eluted with EtOAc in hexane) to give the title compound (4.53 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a vial containing 7-chloro-6-nitrothieno[3,2-b]pyridine (128.7 mg, 0.5996 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 297.6 mg, 1.486 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (179.9 mg, 1.392 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (210.1 mg, 93%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C>C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
tert-Butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (691 mg, 2.00 mmol) was dissolved in ethyl acetate (50 ml), and a solution of 4 N hydrogen chloride in ethyl acetate (11 ml) was added thereto, followed by stirring at room temperature for 1 hour and half. Diethyl ether (20 ml) was poured to the reaction mixture, and a solid was separated by filtration, which was dissolved in an aqueous 1 N sodium hydroxide solution (7 ml). Water was poured to the reaction mixture, and the resulting solution was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 396 mg (80.8%) of the desired product as an oil.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[NH3:13]>>[NH2:13][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: N
Reactant: COC(=O)N1CCCC2(CO2)C1
Product: COC(=O)N1CCCC(O)(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.1 g (53.2 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.