Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14](S(C)(=O)=O)[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[NH3:26]>O1CCOCC1>[CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:26])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: N
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Yield: 100 %

Procedure:
6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17) (30 mg) and concentrated NH3 (0.75 mL) were stirred in 1,4-dioxane (3 mL) for 1 hour. The solvent was evaporated and the resultant residue dissolved in a small volume of DCM. Isohexane was then added and the resultant solid filtered and dried in vacuo to give the title compound as a pale yellow solid (25 mg, 100%);
Reaction SMILES: N1CCCCC1.O[CH:8]=[C:9]([CH3:13])[C:10](=O)[CH3:11].[Na].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16]>C(O)(=O)C.O>[OH:19][C:18]1[N:20]=[C:10]([CH3:11])[C:9]([CH3:13])=[CH:8][C:17]=1[C:15]#[N:16]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(C)=CO
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(C#N)c(O)nc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (7.93 mL) was treated sequentially with piperidine (13.6 mL), water (208 mL), 4-hydroxy-3-methylbut-3-en-2-one, sodium salt (31.7 g, 0.257 mol) then 2-cyanoacetamide (23.8 g, 0.283 mol) then heated to reflux for 6 hours. The reaction mixture was then cooled to <20° C., treated with acetic acid (28.3 mL), stirred for 10 minutes at 0° C., then filtered and washed with water (200 mL) to yield 2-hydroxy-5,6-dimethylnicotinonitrile. To the wet solid was added 6N hydrochloric acid (200 mL) and the mixture was heated to reflux for 3 days. The cooled reaction mixture was poured into ice-water and basified with concentrated ammonium hydroxide (200 mL) and stirred for 10 minutes. The mixture was filtered, washed with water and dried under vacuum at 60° C. to yield 5,6-dimethylpyridin-2-ol (9.57 g, 22%). 400 M Hz 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 7.19 (d, 1H), 6.04 (d, 1H), 2.09 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: C1CCNCC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCCCC4)c3)c2o1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.0 mg (0.23 mmol) of piperidine are reacted together by general method E. 16.4 mg (27.6% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33]
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1Cl)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2Cl)c1
Yield: 46.2 %

Procedure:
Using a procedure similar to that described in Example 11, but starting with 2-[2-amino-N-(2-chlorophenyl)acetamido]-N-methyl-N-phenylacetamide (3.4 g) and 3-methylphenyl isocyanate (1.4 g), and after recrystallisation in acetonitrile, 2-{N-(2-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (2.2 g), m.p. 180° C., is obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:30]=[CH:29][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C(Cl)Cl.C1COCC1>[Cl:31][C:21]1[N:13]([CH2:12][C:11]2[CH:29]=[CH:30][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)=[CH:9][CH:10]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:22])[N:18]([CH3:23])[C:17](=[O:24])[N:16]2[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107 %

Procedure:
2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (450 mg, 1.1 mmol) and hexachloroethane (523 mg, 2.2 mmol) are dissolved in 5 mL of methylene chloride, and then 1.0 M LiHMDS (2.2 mL, 2.2 mmol) in THF is added dropwise. After the reaction mixture is stirred at room temperature for 10 min, water is added, and then extracted with methylene chloride three times. The combined organic phase is evaporated to dryness to give 520 mg of crude product as off-white solids, which is used in the next step without further purification. MS (ESI) m/z 442.2 [M+H]+.
Reaction SMILES: ClC(=C1[C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)CC2)CC3)CC1)C(Cl)S(C1C=CC=CC=1)=[O:5].C1COCC1.C[O-].[Na+].[Cl:41][CH:42](S(C1C=CC=CC=1)=O)[C:43]([O:64][CH3:65])=[C:44]1[C@:61]2([CH3:62])[C@H:47]([C@H:48]3[C:58](=[CH:59][CH2:60]2)[C@:56]2([CH3:57])[C:51](=[CH:52][C:53](=[O:63])[CH2:54][CH2:55]2)[CH2:50][CH2:49]3)[CH2:46][CH2:45]1>CO.O.CC(C)=O>[Cl:41][CH:42]=[C:43]([O:64][CH3:65])[C@:44]1([OH:5])[C@:61]2([CH3:62])[C@H:47]([C@H:48]3[C:58](=[CH:59][CH2:60]2)[C@:56]2([CH3:57])[C:51](=[CH:52][C:53](=[O:63])[CH2:54][CH2:55]2)[CH2:50][CH2:49]3)[CH2:46][CH2:45]1
Reactant: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=CCl)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C

Procedure:
20,21-Dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VII, Example 2, 3.0 g) dry THF (36 ml), methanol (7.5 ml) and acetone (6 ml) are cooled to 0° under nitrogen and sodium methoxide in methanol (25%, 2.8 ml) is added with stirring. After 1 hour of stirring, TLC analysis shows complete conversion of the dichloro starting material (VI) to 21-chloro-20-methoxy-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VIII, Example 3). The mixture is brought to 20°-25° and stirred for 22 hours and then warmed to 30°-35° for 5 hours. The mixture is diluted with water (100 ml) and extracted with ethyl acetate-methylene chloride (2×75 ml). The organic extracts are combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate is triturated with hexane/ethyl acetate (85/15, 25 ml) to give the title compound, mp 197°-199°; NMR (CDCl3) 0.68, 1.35, 3.97, 5.55 and 5.73δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](NC(=O)C(Cl)(Cl)Cl)([CH3:15])([CH3:14])[CH3:13].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C1CCCCC1.C(Cl)Cl>[C:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(C)(C)NC(=O)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 3-bromo-phenyl-acetic acid (10 gm, 46.5 mmol) and methylene chloride (47 mL) was added a solution of t-butyl-2,2,2-trichloroacetamidate (20.3 g, 93.0 mmol) and cyclohexane (186 mL) followed by borontrifluoride etherate (0.93 mL, 7.3 mmol). After stirring overnight, solid sodium bicarbonate was added and the reaction then filtered through a pad of silica gel utilizing methylene chloride as solvent. Concentration gave 9.11 g (72%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]S(C)(=O)=O)=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[NH:8]2)=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=1.O1CCCC1.CO.[OH-].[K+]>O>[F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([OH:18])=[O:17])[NH:8]2)=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)c(F)c(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc3cc(C(=O)O)[nH]c3c(O)c2F)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.8 %

Procedure:
To a mixture of ethyl 6-fluoro-7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.1 g), tetrahydrofuran (25 mL) and methanol (25 mL) was added a solution of potassium hydroxide (85%, 1.9 g) in water (15 mL). The mixture was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light pink solid, which was washed with ethyl acetate-hexane to give the title compound (2.52 g, 100%) as a light pink solid. MS 365 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1OS(C(F)(F)F)(=O)=O)[CH3:2].[Cl:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.CCO.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1[C:42]1[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=1)[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 50.3 %

Procedure:
A solution of (4-methoxy-benzyloxy)-(5-methoxy-3-methyl-1-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid ethyl ester (128 mg, 0.236 mmol), 4-chlorophenylboronic acid (74 mg, 2 equiv), EtOH (0.5 mL), K2CO3 (2 M, 0.5 mL), and toluene (1.3 mL) were degassed with argon at room temperature in a Schlenk tube. Pd(dppf)Cl2 was then added (17 mg) and the tube sealed. The reaction was heated to 60° C. for 14 hours. Analysis of the reaction mixture by LCMS showed 40% conversion, with visual analysis showing significant amount of palladium black. The crude mixture was filtered via syringe through a microfilter into a new sealable tube charged with Pd(PPh3)4. The tube was sealed and heated to 100° C. for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was concentrated, and the crude residue purified by flash column chromatography to give the desired product (60 mg, 50% yield). LCMS-ESI+ (m/z): [M+Na]+ calcd for C30H29ClNaO5: 527.99. Found: 527.44.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([N:21]2[CH2:26][C@H:25]([CH3:27])[NH:24][CH2:23][C@@H:22]2[CH3:28])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1C[CH2:40][CH2:39][CH2:38]1>>[CH2:40]([N:24]1[CH2:23][C@H:22]([CH3:28])[N:21]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:30][CH:29]=2)[CH2:26][C@@H:25]1[CH3:27])[CH:39]=[CH2:38]
Reactant: C1CCOC1
Reactant: C[C@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCN1C[C@H](C)N(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C

Procedure:
The purified benzhydrylpiperazine (1.51 g, 3.1 mmol) was dissolved in 20 mL of dry tetrahydrofuran with 0.27 mL (3.2 mmol) of alkyl bromide and 1.6 g (15.5 mmol) of sodium carbonate and heated at reflux overnight under nitrogen. The cooled reaction solution was filtered and the solvent removed to give 1.62 g of crude (2S,5S)-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a yellow oil.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([OH:26])[C:20]([CH3:28])([CH3:27])[CH2:19]2)[N:10]=[C:9]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][C:38]([CH3:41])([CH3:40])[N:37]([OH:42])[C:36]([CH3:44])([CH3:43])[CH2:35]2)[N:8]=1.OO.S([O-])([O-])=O.[Na+].[Na+].[CH2:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>O.C(#N)C>[Cl:6][C:7]1[N:8]=[C:9]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:35][C:36]([CH3:44])([CH3:43])[N:37]([O:42][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:38]([CH3:41])([CH3:40])[CH2:39]2)[N:10]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:19][C:20]([CH3:28])([CH3:27])[N:21]([O:26][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:22]([CH3:24])([CH3:25])[CH2:23]2)[N:12]=1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Agent: CS(=O)(=O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Temperature: 52 °C
Yield: 50 %

Procedure:
A solution of 0.188 g (0.676 mmol) of ferrous sulfate heptahydrate and 0.25 g (2.6 mmol) of methanesulfonic acid in 2 ml of water is added to a mixture of 5.00 g (8.83 mmol) of 2-chloro-4,6-bis[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-s-triazine, 29 ml of acetonitrile, and 18 ml of cyclohexane. The reaction mixture is heated to 52° C. A solution of 4.87 g (72 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture over 2.25 hours while the temperature is brought to and maintained at 62° C. After the peroxide is added, the reaction mixture is stirred at reflux for 45 minutes, then cooled prior to decomposing residual peroxide with aqueous sodium sulfite. Work-up and purification according to the procedure of Example 5 afford 3.23 g (50% yield) of the title compound, a white glass. Structure is verified by NMR and ms analysis.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Product: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 26 %

Procedure:
Prepared according to the experimental procedure described in Preparation 61a from 1.07 g (3.39 mmol) of 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide and 1.65 g (3.73 mmol) of (S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid. After stirring the reaction mixture overnight, an excess of an additional 1.65 g (3.73 mmol) of the acid was added and the reaction stirred for yet 24 hours more. After precipitation and filtration of the product, two purification steps were needed. First by flash chromatography (70% to 100% DCM/hexanes) and a second purification by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%). 494 mg (26% yield) of the title compound were isolated as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1.NOS(O)(=O)=O.C(=O)([O-])O>>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]#[N:2])=[N:6][CH:7]=1
Reactant: CN(C)/C=C/c1ccncn1
Agent: NOS(=O)(=O)O
Agent: O=C([O-])O
Product: N#CCc1ccncn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To 70 mL of an aqueous solution containing 5 g of dimethyl-[(E)-2-(4-pyrimidinyl)vinyl]amine, 9.48 g of hydroxylamine-O-sulfonic acid was added and stirred at 50° C. for 30 minutes. The reaction solution was made basic by addition of saturated aqueous hydrogen-carbonate solution under cooling with ice, and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and removed of the solvent by distillation under reduced pressure. Thus obtained residue was purified on 30 g silica gel column chromatography (eluent, chloroform:methanol=30:1) to provide 1.56 g (yield: 39%) of the title compound as pale yellow crystal.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:27][CH:28]=1
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc2oc(Cc3ccc(O)cc3)c(C)c12
Reaction time: 0.25 h

Procedure:
Under nitrogen, ethanethiol (3.1 gm; 50 mmoles) was added dropwise over 5 minutes to a mixture of 99% sodium hydride (1.2 gm; 50 mmoles) in dimethylformamide (100 mL). After stirring for 15 minutes, a solution of 2-(4-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (2.1 gm; 6.7 mmoles) in dimethylformamide (DMF) (25 mL) was added in one portion. The mixture was refluxed for 1.5 hours, cooled, acidified with 20% citric acid and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting oil crystallised on standing at room temperature overnight. The crystals were slurried with hexane, filtered, washed with hexane, and air-dried to yield 2-(4-hydroxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 138°-142° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21]CC)[O:18]CC)=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:35]2[N:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:12]2[CH:13]=[CH:14][C:15]([CH2:16][P:17](=[O:18])([OH:21])[OH:24])=[CH:25][CH:26]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:35]2[N:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc(OC)cc2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc(CP(=O)(O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.6 %

Procedure:
diethyl 4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)benzylphosphonate (32-g, 450 mg, 0.8 mmol) was dissolved in DCM (10 ml), TMSBr (1.8 g, 12 mmol) was then added, the reaction mixture was stirred for 14 h at ambient temperature, monitored by TLC. The resulting mixture was concentrated under reduce pressure, the residue was dissolved in CH3CN (5 ml), diluted with water (10 ml), stirred for 10 min, filtered, washed with water, purified by pre-HPLC, the pure product 32-1 was obtained as a white solid (104 mg, 26% yield). 1H NMR (300 MHz, CD3OD) δ2.97-3.04 (d, J=21.6 Hz 2H) 3.67 (s, 1H) 6.17 (s, 1H), 6.78-6.81 (m, 2H) 7.12-7.20 (m, 6H), 7.80-7.90 (m, 1H), 8.49-8.58 (m, 1H), 8.75 (s, 1H), 9.28 (m, 1H). LC-MS 508 [MH]+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27]O)[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27][N:34]1[C:30](=[O:40])[C:31]2[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]1=[O:35])[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)(C)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (0.63 ml, 4 mmol) is added to a suspension of ((S)-1-Hydroxymethyl-3,3-dimethyl-pent-4-enyl)-carbamic acid tert-butyl ester (1 g, 4 mmol), phthalimide (588 mg, 4 mmol) and PS-triphenylphosphine (3.72 g, 8 mmol) in THF (50 ml) and the resulting solution is stirred at room temperature overnight. The resin is removed by filtration, and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields [(S)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pent-4-enyl]-carbamic acid tert-butyl ester as a white solid; [M+H—BOC]+ 273.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22](C(OCC)=O)[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:30])[C:6](C(OCC)=O)=[CH:5]2)[CH2:3][CH2:2]1>Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][NH:22][CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:30])[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN(C)C(=O)OCC)C3)c(F)cc2c1=O
Agent: Cl
Product: CNCC1CN(c2c(F)cc3c(=O)ccn(C4CC4)c3c2F)CCO1
Yield: 90.4 %

Procedure:
A suspension of 2.5 g of ethyl 1-cyclopropyl-6,8-difluoro-7-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylate in 20 ml of 10% aqueous hydrochloric acid is refluxed for 12 hours. The reaction mixture is concentrated under reduced pressure, and to the obtained crystals is added ethanol. The crystals are collected by filtration with suction, washed with ethanol and then dried to give 1.6 g of 1-cyclopropyl-6,8-difluoro-7-[2-(methylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-[carboxylic acid. hydrochloride in 73% yield, melting at 289°-290° C. with decomposition.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([Cl:17])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C=CCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The HCl salt of 4-Piperidin-1-yl-but-2-enoic acid (250 mg, 1.48 mmol) was dissolved in dichloromethane (15 mL). Dimethylformamide (3 drops) was added. Oxalyl chloride (155 μL, 1.77 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was used as is.