Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:27]=2[C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])[C:22]([Cl:39])=[CH:21][N:20]=1>>[Cl:39][C:22]1[C:23]([NH:25][C:26]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:27]=2[C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 8-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow solid (93 mg, 43%). m.p.=237-241° C.; LCMS (m/e) 535 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.12 (s, 1H), 7.49 (s, 1H), 7.40 (d, 1H, J=7.4 Hz), 7.36-7.25 (m, 2H), 7.21 (d, 1H, J=8.9 Hz), 7.13 (d, 1H, J=8.3 Hz), 6.89 (s, 1H), 6.34-6.27 (m, 1H), 4.19-4.15 (m, 2H), 3.77-3.65 (m, 2H), 2.34-2.21 (m, 3H), 2.10-1.93 (m, 2H), 1.33 (s, 6H), 1.20 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>CS(C)=O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of 9.40 grams (g) (0.0576 mole) of 3,4-dichlorophenol dissolved in 150 milliliters (ml) of dimethyl sulfoxide (DMSO) was added 2.30 g (0.0576 mole) of sodium hydroxide (NaOH). The mixture was heated to 60° C. and 10.0 g (0.0524 mole) of 4-chlorophenyl methyl sulfone was added. The reaction mixture was heated at 165° C. for 2.5 hours (hrs) and cooled. The mixture was poured into water and the crystalline product collected by filtration, washed well with water and dried, which gave 12.8 g (77.1% yield) of product. Recrystallization from ethanol afforded purified 4-(4-(methylsulfonyl)phenoxy)-1,2-dichlorobenzene, melting at a melting point (mp) of 124.5°-125.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:30][O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12>CC(C)=O.Cl>[O:29]1[CH2:30][CH:24]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCOCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNCCOC1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
tert-butyl 6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1,4-oxazepane-4-carboxylate is dissolved in acetone and 6N aqueous hydrochloric acid. The reaction is then heated at 45° C. which yielded a precipitate. After 2.5 hours, the precipitate is collected by vacuum filtration, washed with a minimal amount of acetone and dried on the lyophilizer to afford title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.Br.[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20]C(=N)N)[N:15]=[CH:14]1.[OH-].[Na+]>C(O)C.O>[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N=C(N)SCCc1c[nH]cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(SCCc2c[nH]cn2)nc1

Procedure:
A hot solution of 0.2 g (1.3 mmol) of 2-chloro-5-nitropyridine in 5 ml of ethanol is added to a solution of 0.2 g (1.1 mmol) of S-{2-[1H-imidazol-4-yl]ethyl}isothiourea dihydrobromide in 2 ml of water. The resulting suspension is stirred under nitrogen. The reaction mixture is cooled to 0°-5° C. and a solution of 4 molar equivalents of sodium hydroxide (0.16 g) in 2 ml of water is added dropwise under N2. The reaction mixture is stirred for 1 h at the same temperature and for 3 h at 21° C. The reaction mixture is evaporated to dryness and the residue is subjected to column chromatography (silica gel) eluted with a gradient mixture of chloroform and methanol (1-10%) to provide the title compound which is then crystallized from 2-propanol, M.p.: 147°-148° C.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([C:7]1([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9][C:8]1=[O:15])[CH3:6]>[Cl-].C([N+](CC)(CC)CC)C.CN(C)C=O>[OH:4][CH:2]([CH3:3])[CH2:1][N:11]1[C:12](=[O:13])[C:7]([CH2:5][CH3:6])([CH2:16][CH3:17])[C:8](=[O:15])[N:9]([CH2:1][CH:2]([OH:4])[CH3:3])[C:10]1=[O:14]
Reactant: CCC1(CC)C(=O)NC(=O)NC1=O
Reactant: CC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N(CC(C)O)C1=O
Temperature: 100 °C
Yield: 102.7 %

Procedure:
40.7 g (0.7 mol) of propene oxide are added dropwise over the course of 1 hour to a mixture of 55.3 g of 5,5-diethylbarbituric acid (0.3 mol), 2.77 g of tetraethylammonium chloride (5 mol per cent) and 400 ml of dimethylformamide at 35° C. whilst stirring. Thereafter the mixture is gradually heated to 100° C. After 7 hours' stirring at 100° C. the mixture is worked-up in accordance with example 1. 92.5 g of crude 1,3-di(β-hydroxy-n-propyl)-5,5-diethylbarbituric acid (99.5 % of theory) are obtained. The product boils at 138°-148° C. under 0.08 mm Hg; 75.2 g of pure product 80% of theory) are obtained.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[CH3:28][CH:29]([C@H:31]1[NH:35][CH2:34][C@H:33]([OH:36])[CH2:32]1)[CH3:30].[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:35]4[CH2:34][C@H:33]([OH:36])[CH2:32][C@H:31]4[CH:29]([CH3:30])[CH3:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1C[C@@H](O)CN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (150 mg, 0.337 mmol), (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol(TFA salt, 164 mg, 0.675 mmol), potassium fluoride (98 mg, 1.68 mmol), DMSO (1 mL), and N,N-diisopropylethylamine (0.589 mL, 3.37 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H33ClN6O [M+H]+ 493. found 493.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[O:7][C:8]([CH3:33])([CH3:32])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC4C=CC(OC)=CC=4)=[CH:13][C:12]3=[O:31])[C:5]=2[CH:4]=1)#[N:2].O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[C:1]([C:3]1[CH:35]=[CH:34][C:6]2[O:7][C:8]([CH3:32])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][C:12]3=[O:31])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(COCCCCc2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)C=C(n2ccc(CCCCO)cc2=O)c2cc(C#N)ccc2O1
Yield: 92.7 %

Procedure:
In 24 ml of methylene chloride, is dissolved 1.13 g of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 46. Then, 1.33 ml of water is added. Then, 0.82 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added at room temperature and the resulting mixture is reacted at that temperature for 40 minutes. After stopping the reaction by adding water, the reaction mixture is extracted with methylene chloride. The organic layer is washed successively with 0.1M aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/10 mixture of methanol/methylene chloride as a developing solvent. Thus, 0.78 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(4-hydroxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[CH:20][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]=2[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Reactant: O=CNc1ccccc1
Product: COc1ccc2ncn(-c3ccccc3)c2c1
Yield: 55.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 2-Iodo-4-methoxy-1-nitrobenzene (140 mg, 0.5 mmol) and N-Phenyl-formamide (73 mg, 0.6 mmol) as starting materials to yield the title compound as viscous oil (62 mg, 56%). 1H NMR (DMSO) δ 2.58 (s, 3 H), 2.64 (s, 3 H), 7.37 (d, J=8.1 Hz, 1 H), 7.44 (dd, J=8.1, 7.3 Hz, 1 H), 7.48-7.52 (m, 1 H), 7.54 (d, J=8.8 Hz, 2 H), 7.61 (d, J=8.8 Hz, 2 H), 7.86 (d, J=7.3 Hz, 1 H).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:45][C:46](=[N:49]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[C:29]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH:16][C:46](=[NH:45])[NH2:49])=[O:10])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 59.8 %

Procedure:
Prepared according to the method described in Example 1(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (0.5 g; 1.12 mmol), N,N'-bis(Cbz)-S-methylisothiourea (0.603 g; 1.68 mmol), DiPEA (0.2 mL) and DMF (15 mL) yielding 0.351 g of sub-title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][CH3:18])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (255 mg) in anhydrous DMF (1 ml) was added dropwise to a suspension of sodium hydride (40 mg) in anhydrous DMF (1 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Ethyl iodide (0.10 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature overnight. Saturated brine was added thereto and the resulting mixture was extracted with chloroform. Organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=1/10) to obtain N-(4-iodophenyl)-N-ethylpyrimidin-2-amine (264 mg). NMR (H1, CDCl3): δ 1.23 (3H, t, J=6.8 Hz), 4.01 (2H, q, J=6.8 Hz), 6.57 (1H, t, J=4.9 Hz), 7.03-7.06 (2H, m), 7.70-7.74 (2H, m), 8.32 (2H, d, J=4.9 Hz)
Reaction SMILES: C[Si](Cl)(C)C.[CH2:6]([O:8][C:9](=[O:14])[C:10](Br)([F:12])[F:11])[CH3:7].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28]C2C3N=NNC=3C=CC=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>C1COCC1.[Zn]>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:14])([F:12])[F:11])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3[nH]nnc23)CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a suspension of zinc dust (1.93 g, 29.5 mmol) in dry THF (30 mL), under nitrogen, was added TMS-Cl (trimethylsilyl chloride) (1.28 g, 11.8 mmol). The reaction mixture was stirred for 15 min, and then ethylbromodifluoroacetate (4.49 g, 22.1 mmol) was slowly added, followed 15 min later by a solution 4-benzotriazol-ylmethylpiperazine-1-carboxylic acid tert-butyl ester (4.68 g, 14.8 mmol). After, 3 h stirring at room temperature, the mixture was poured onto 5% aqueous NaHCO3 (40 mL) and filtered on celite. The filtrate was diluted with ethyl acetate and organic layer was separated, dried (MgSO4) and concentrated to give an oil which was purified by flash chromatography (Hexane-Ethyl acetate (8:2) to give 1.05 g of 4-(2-ethoxycarbonyl-2,2-difluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)s2)c(C)[nH]c1=O
Yield: 99 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(4-fluorophenyl)piperazine as described in Step 5, Example 24 to give the title compound as a solid (99% yield). LC/MS: RT 3.92 min; m/e 462 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 7.65 (1H, d); 7.38 (1H, s); 7.30 (1H, d), 6.94 (4H, m), 3.12 (8H, m), 2.39 (2H, q), 2.33 (3H, s), 1.07 (3H, t); 19F NMR −123.8.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2Cl)=[CH:4][C:3]=1[O:20][CH3:21]>C(O)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[O:20][CH:3]([CH3:4])[CH3:2])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1Br
Solvent: CC(C)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1Br

Procedure:
Similar procedure as described in example 376 was used, starting from (7-Bromo-1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropanol to give (7-Bromo-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 391 (MH+).
Reaction SMILES: [O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[CH:3][CH:4]=[CH:5]2.[Br:21]Br>C(O)(=O)C>[Br:21][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][CH:13]4[CH:12]([OH:20])[CH2:11][CH2:10][C@@H:9]35
Reactant: BrBr
Reactant: CN1CC[C@]23c4c5cccc4OC2C(O)CC[C@H]3[C@H]1C5
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(Br)c4OC2C(O)CC[C@H]3[C@H]1C5
Reaction time: 1 h

Procedure:
3.1 g (11.4 mmol) of 4,5-epoxy-17-methylmorphinan-6-ol were dissolved in 150 ml of glacial acetic acid and 11.4 ml of a 1M solution of Br2 in AcOH were added dropwise. After 1 h, AcOH was removed in vacuo, the residue was taken up with water, the aqueous solution was brought to pH 7 with a saturated NAHCO3 solution and extracted with AcOEt. The organic phase was dried over NA2SO4, the solvent was removed in vacuo, yielding 3.6 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.C1C(=O)N(Br)C(=O)C1.[CH3:43][CH:44]([CH3:48])[C:45](=[S:47])[NH2:46]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:47][C:45]([CH:44]([CH3:48])[CH3:43])=[N:46][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.3 %

Procedure:
In a 250 mL flask was placed N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (4 g, 9.05 mmol) and DMF (60 mL) was added. NBS (1.62 g, 9.10 mmol) was added and, after stirring at rt for 40 min, 2-methylpropanethioamide (1.4 g, 13.6 mmol), prepared by a procedure analogous to Intermediate 1, was added. After 4 h at rt, the reaction mixture was poured into 800 mL of EtOAc and washed 4 times with 250 mL of H2O, washed once with 200 mL of brine, and dried over NaSO4. Silica gel was added and the volatiles were removed under reduced pressure. Column chromatography with 10% to 60% EtOAc:Hexane gave 2.15 g (45%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.06 (d, J=5.3 Hz, 1H), 8.12-8.30 (m, 1H), 7.93-8.06 (m, 2H), 7.84 (t, J=7.9 Hz, 1H), 7.75 (t, J=9.2 Hz, 2H), 7.37 (d, J=5.3 Hz, 1H), 3.77-3.93 (m, 1H), and 1.89 (d, J=6.8 Hz, 6H). MS (ESI): 524 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:28][C:29](=O)[NH:30][C:31]1[N:32]([CH3:40])[N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([NH:1][C:2]2[CH:24]=[CH:23][C:5]([O:6][CH:7]3[CH2:8][CH2:9][N:10]([C:13](=[O:14])[C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:22])[CH2:11][CH2:12]3)=[CH:4][CH:3]=2)=[O:28])[N:32]([CH3:40])[N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Nitrogen gas is bubbled through a solution of [4-(4-amino-phenoxy)-piperidin-1-yl]-(2,6-dichlorophenyl)-methanone (47 mg, 0.12 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (42 mg, 0.12 mmol) in DMSO (1.5 mL) for 5 min. Next, N,N-diisopropylethylamine (40 μL, 0.24 mmol) is added. The reaction mixture is stirred at 60° C. for 6 hours. Then, DMSO is removed by passing the reaction mixture through an SCX column. The crude product is obtained by eluting the SCX column with 2M ammonia in methanol and purifying the residue on silica gel with ethyl acetate-hexanes (25%) to give a white solid (ES+(m/z) 544.2 [M+H]).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH:14]=[CH:21][N:24]([CH3:26])[CH3:25])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(C=CN(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 57.7 %

Procedure:
A mixture of 3-methyl-2,6-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water and the precipitate was collected via filtration and washed with water to give 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (25 g, 58%).
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH:16]([CH2:22][CH3:23])[CH:17]([CH3:21])[CH2:18][CH2:19][CH3:20])[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CO>[C:1]1([N:7]=[C:8]([S:15][CH:16]([CH2:22][CH3:23])[CH:17]([CH3:21])[CH2:18][CH2:19][CH3:20])[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(C)C(CC)SC(C#C[Si](C)(C)C)=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#CC(=Nc1ccccc1)SC(CC)C(C)CCC
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
1-ethyl-2-methylpentyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.60 g) was dissolved to methanol (12 mL), small amount of potassium carbonate was added to the solution under ice-cooling, and then stirred for 30 minutes. The reaction mixture was poured into saturated aqueous solution of sodium chloride. It was extracted with ethyl acetate. Obtained organic layer was washed with water, dried, and the solvent was distilled off to obtain 1-ethyl-2-methylpentyl N-(phenyl)thiopropynimidate (0.44 g).