Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=O)=[CH:8]1.[CH3:19][O:20][C:21]1[CH:27]=[C:26]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)[CH:25]=[CH:24][C:22]=1[NH2:23].N1C=CC=CC=1>ClCCl.O1CCCC1.CN(C)C=O.C(OCC)(=O)C.O>[CH3:19][O:20][C:21]1[CH:27]=[C:26]([B:28]2[O:29][C:30]([CH3:35])([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32]2)[CH:25]=[CH:24][C:22]=1[NH:23][C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1)=[O:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
Oxalyl chloride (0.07 mL, 0.79 mmol) was added into a solution of indole-3-carboxylic acid (0.12 g, 0.72 mmol) in dichloromethane (4 mL) and tetrahydrofuran (3 mL) at 0° C. N,N-dimethylforamide (3 drops from 0.1 mL syringe) was added and the mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 20 minutes. The solvents and excess of reagents were evaporated under reduced pressure. The residue was taken into dichloromethane (2 mL) and the resulting solution (1.5 mL) was added into a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.09 g, 0.36 mmol) and pyridine (1 mL) in dichloromethane (2 mL). The mixture was stirred at ambient temperature overnight. The acid chloride solution in dichloromethane (0.3 mL) was added in and the mixture was stirred overnight. Water (a drop) was added in. The volatile components were evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were combined and washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and the solvent of the filtrate was evaporated to yield the crude which was purified by flash column chromatography on silica using n-heptane: ethyl acetate (2/1) as a mobile phase to yield N3-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-3-indolecarboxamide (0.11 g, 0.28 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.65 (m, 3H), 8.13 (d, 1H), 7.95 (s, 1H), 7.50 (m, 2H), 7.33(m, 3H), 4.02 (s, 3H), 1.36 (s, 12H); MS: MH+ 393.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:6]1=[O:21].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[C:6]1=[O:21]
Reactant: COC(=O)c1ccc(-c2cccn(CCN(C)C)c2=O)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCCN(CCN(C)C)C2=O)cc1
Yield: 88.4 %

Procedure:
Methyl 4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoate (490 mg) was dissolved in acetic acid (20 mL), and platinum oxide (74 mg) was added, followed by stirring in a hydrogen atmosphere (1 atm.) at room temperature for 15 hours. The vapor in the reactor was purged with argon, then the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was concentrated under reduced pressure, followed by two times azeotropy with toluene. An aqueous saturated sodium hydrogencarbonate solution was added to the residue, followed by two times extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain methyl 4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoate (439 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:17])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 1.96 g (8.46 mmol) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidine-5-carbonitrile in 8 ml DMF was added dropwise a solution of 1.58 g (8.88 mmol) N-bromosuccinimide in 7 ml DMF and stirring continued at room temperature for 1 hour. The reaction mixture was then poured into 500 ml ice-water and the resulting precipitate collected by filtration and washed with water and then ether to afford 2.50 g (95%) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light brown crystalline solid. ES-MS m/e (%): 311 ([M{81Br}-H]−, 100), 309 ([M{79Br}-H]−, 95).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27]OS(C)(=O)=O)[CH:12]=2)=[CH:7][CH:6]=1.[CH3:33][CH:34]1[CH2:39][NH:38][C:37]([CH3:41])([CH3:40])[CH2:36][N:35]1[CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:38]3[CH2:39][CH:34]([CH3:33])[N:35]([CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[CH2:36][C:37]3([CH3:40])[CH3:41])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC1CNC(C)(C)CN1Cc1cccnc1
Reactant: COCOc1ccc(-c2cc(COS(C)(=O)=O)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(-c2cc(CN3CC(C)N(Cc4cccnc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Temperature: 140 °C
Yield: 36.3 %

Procedure:
To a solution of 150 mg of methanesulfonic acid 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl ester, and 85 mg 2,5,5-trimethyl-1-(pyridin-3-ylmethyl)piperazine in 4 ml of dry THF were added 0.28 ml of DIPEA. The reaction was heated to 140° C. for 60 min in a microwave reactor. The reaction was diluted with ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphaste, filtrated and concentrated. The resulting oil was purified by chromatography (silica, heptanes/ethyl acetate). 69 mg of the title compound were obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[CH3:13][NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:13][NH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
To a solution of 1,4-dioxaspiro[4,5]decan-8-one (10.0 g) and acetic acid (4.4 ml) in dichloromethane (128 ml) were added methylamine hydrochloride (5.19 g) and sodium triacetoxyborohydride (16.3 g), and stirred at room temperature for 2.5 hours. After completion of the reaction, 4 N aqueous solution of sodium hydroxide (90 ml) was added thereto, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and then the solvent was evaporated to give (1,4-dioxaspiro[4,5]dec-8-yl)methylamine as an orange oil (11.0 g).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)#[N:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:14]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:15][CH2:16]1)#[N:10]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(CC(=O)C(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (88 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 8.5 hours. Water was added to the reaction solution, the precipitated solid was filtered, and washed with water and ethanol to give the titled compound (271 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[C:8]([C:16]([NH2:18])=[O:17])[CH:7]=[N:6][N:5]2[CH:19]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:13]1([C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:19]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:16]([NH2:18])=[O:17])[CH3:12])[CH2:15][CH2:14]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)C1CC1
Yield: 49.3 %

Procedure:
A degassed solution of (R)-6-bromo-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 4, 20 mg, 0.062 mmol), phenylboronic acid (22.64 mg, 0.186 mmol), potassium carbonate (0.077 mL, 0.155 mmol, 2M) and palladium tetrakis(triphenylphosphine) (4.29 mg, 3.71 μmol) in DME (1 mL) was heated to 90° C. for 1 hr. The reaction mixture was concentrated and redissolved in 1 mL of MeOH, and purified by reverse-phase preparative HPLC (condition C) to yield the title compound (9.8 mg, 48%). HPLC (condition I): retention time=2.49 min. LC/MS (M+H)+=321.1. 1H NMR (500 MHz, MeOD) δ ppm 8.04 (1 H, s), 7.82 (1 H, d, J=1.7 Hz), 7.61 (1 H, d, J=1.1 Hz), 7.59 (1 H, d, J=0.8 Hz), 7.56 (1 H, s), 7.37 (2 H, t, J=7.8 Hz), 7.21-7.26 (1 H, m), 4.05 (1 H, quin, J=6.4 Hz), 1.44 (3 H, d, J=6.4 Hz), 1.08-1.17 (1 H, m), 0.52-0.62 (2 H, m), 0.35-0.41 (2 H, m).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:6]([CH3:5])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: Cc1ccccc1C=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of aluminum chloride (57.93 g, 434.46 mmol) in methylene chloride (200 mL) is added at 0° C. over 45 min o-methylbenzaldehyde (30 g, 249.69 mmol). To the resulting brown mixture is further added a methylene chloride solution (200 mL) of bromine (12.71 mL, 249.69 mmol) over 3 h and the reaction mixture is allowed to reach room temperature overnight. The reaction mixture is then poured into ice (600 g) and the aqueous layer is extracted twice with methylene chloride. The combined organic extracts are washed with a saturated aqueous solution of NaHCO3, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into hexane and the precipitate is filtered, washed with hexane (this protocol is repeated twice) and dried under high vacuum to afford the title compound as a mixture of two regioisomers: 5-bromo-2-methyl-benzaldehyde and 3-bromo-2-methyl-benzaldehyde in a 80/20 ratio: MS 197.0, 199.0 [M−H]. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.52 min.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH:42]2[C:43](=[O:47])[NH:44][CH2:45][CH2:46][N:41]2[CH2:40][CH2:39][O:38]1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:45][CH2:46][N:41]4[CH:42]([CH2:37][O:38][CH2:39][CH2:40]4)[C:43]3=[O:47])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NCCN2CCOCC12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCOCC3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A 8 ml sealed vial was charged with 150 mg (0.281 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 120 mg (0.768 mmol) of hexahydropyrazino[2,1-c][1,4]oxazin-9(6H)-one (D7), 60 μL (0.563 mmol) of N,N′-dimethylethylenediamine, 110 mg (0.578 mmol) of copper iodide, 183 mg (0.562 mmol) of cesium carbonate; the reagents were dissolved in 4.5 ml of dioxane. The reaction mixture is stirred overnight at 150° C. The crude was purified by chromatography (silica, cyclohexane/EtOAc 90/10-30/70) affording the title compound as a white solid: 73 mg, 0.111 mmol, 40% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:26]([C:25]1[CH:34]=[CH:35][C:36]([O:38][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[CH:37][C:24]=1[OH:23])(=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1
Yield: 39.8 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole-(2.76 g), 2,4-dihydroxybenzophenone (2.00 g), anhydrous potassium carbonate (1.29 g) and acetone (50 mL) was heated under reflux for 0.15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.72 g, 40%) of 4-[4-(4-benzoyl-3-hydroxyphenoxymethyl)phenoxymethyl]-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 160-161° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:38][CH3:39])=[C:7]([CH2:27][C:28]([N:30]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:32][O:33][CH3:34])=[O:29])[C:8]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:42]I.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:6]([CH2:38][CH3:39])=[C:7]([CH2:27][C:28]([N:30]([CH2:35][CH2:36][O:37][CH3:42])[CH2:31][CH2:32][O:33][CH3:34])=[O:29])[C:8]([C:15](=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(S(C)(=O)=O)cc2)c(CC(=O)N(CCO)CCOC)c1CC
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(S(C)(=O)=O)cc2)c(CC(=O)N(CCOC)CCOC)c1CC
Yield: 21.8 %

Procedure:
(Step 1) 2-[3,5-Diallyloxy-2-ethyl-6-(4-methanesulfonylbenzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-methoxyethyl)acetamide (450 mg, 0.76 mmol) obtained in Example 96, Step 1 was dissolved in N,N-dimethylformamide (10 mL), and a 60% sodium hydride dispersion in mineral oil (50 mg, 1.3 mmol) was added thereto in an atmosphere of argon with stirring under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, and methyl iodide (0.05 mL, 0.8 mmol) was added dropwise thereto, followed by further stirring for 12 hours. After the reaction mixture was ice-cooled, a saturated aqueous solution of ammonium chloride was added thereto to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1) to obtain 2-[3,5-diallyloxy-2-ethyl-6-(4-methanesulfonylbenzoyl)phenyl]-N,N-bis(2-methoxyethyl)acetamide (95 mg, 21%).
Reaction SMILES: C([O:8][CH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][CH:9]1[CH2:10][CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(O)C1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
2.77 g (10 mmol) tert.butyl (3-benzyloxy-cyclobutyl)-carbamate are suspended in 100 ml of methanol and combined with 200 mg palladium hydroxide. The reaction mixture is stirred for 5 h at 45° C. and 45 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed three times with aqueous sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:20]2[C:19]3[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=3[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:16]=2[N:15]=[CH:14][CH:13]=1>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1([O:8][C:14]2[CH:13]=[CH:12][C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:16]=3[N:15]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1(O)CCCNC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(Oc2ccc3c4cc(C#N)ncc4n(COCC[Si](C)(C)C)c3n2)CCCNC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methylpiperidin-3-ol (99 mg, 0.86 mmol) in tetrahydrofuran (3.2 mL) was added sodium hydride as 60% dispersion in mineral oil (35 mg, 0.86 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (141 mg, 0.39 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes before being warmed to 40° C. for 5 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as an orange solid, which was used in the next step without any further purification (52 mg, 30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]Cl.[SH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.[OH-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: ClSc1ccccn1
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCSSc1ccccn1

Procedure:
2.4 g of 2-pyridine sulfenyl chloride are dissolved in 40 ml of methylene chloride, and a solution of 1.75 g of 3-mercaptopropionic acid in 10 ml of methylene chloride is added slowly, whilst stirring and cooling with an ice bath. When the addition is complete, the mixture is stirred at ambient temperature for 15 hours. 50 ml of water are added and the pH is brought to 4.5 by adding 1 N sodium hydroxide solution. The organic phase is separated off and dried over sodium sulphate and the solvent is evaporated off to dryness. An oily product remains and this crystallises (1.8 g). It is purified by dissolution in 16.8 ml of a 0.5 M aqueous solution of sodium bicarbonate. Activated charcoal is added, the solution is filtered and the expected product is then precipitated by adding concentrated acetic acid (0.5 ml) so as to bring the pH to between 3 and 3.5. The precipitate is filtered off and dried under high vacuum and a solid (1.3 g), melting point (capillary method): 62°-64° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:12]([OH:15])[CH:13]=[CH2:14])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:15][C@H:12]([C@@H:11]([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C@@H:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[CH3:10])[CH:13]=[CH2:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C=C[C@H](O)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
To a solution of (3S,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol (2.34 g, 7.64 mmol) in DMF (15.3 mL) was added NaH (0.611 g, 15.3 mmol, 60% dispersion in mineral oil) at 0° C. After 20 min, benzyl bromide (2.27 mL, 19.1 mmol) was added and the reaction was stirred at 0° C. for 20 min, warmed to 45° C., and stirred at this temperature for 16 h. The reaction was cooled to room temperature and quenched with sat. aq. NH4Cl (40 mL). The mixture was extracted with Et2O (3×50 mL), and the combined organics were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using flash column chromatography (120 g SiO2, 0→20% EtOAc/hexanes) to afford the title compound (2.75 g, 6.93 mmol, 91%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 2H), 7.32-7.25 (m, 3H), 7.22-7.17 (m, 2H), 6.87-6.78 (m, 2H), 5.78 (ddd, J=17.4, 9.9, 7.3 Hz, 1H), 5.27-5.18 (m, 2H), 4.58 (d, J=12.4 Hz, 1H), 4.42 (d, J=11.2 Hz, 1H), 4.29 (d, J=11.2 Hz, 1H), 4.26 (d, J=11.9 Hz, 1H), 4.04-3.96 (m, 1H), 3.77 (s, 3H), 3.64 (p, J=6.3 Hz, 1H), 1.73-1.63 (m, 1H), 1.55-1.42 (m, 2H), 1.43-1.21 (m, 3H), 1.15 (d, J=6.3 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 158.92, 139.07, 137.94, 131.19, 129.17, 128.19, 127.77, 127.47, 116.82, 113.65, 81.13, 75.03, 70.36, 70.07, 55.22, 48.17, 38.66, 28.62, 23.67, 22.61, 16.84; ESIMS m/z 419 ([M+Na]+).