Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][C:4](=[N:6][OH:7])[NH2:5].CCN(CC)CC.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(#N)C>[NH2:5][C:4](=[N:6][O:7][CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][C:2]([F:9])([F:8])[F:1]
Reactant: NC(CC(F)(F)F)=NO
Reactant: C#CC(=O)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CON=C(N)CC(F)(F)F
Temperature: 80 °C

Procedure:
Into a flask containing 3,3,3-trifluoro-N′-hydroxypropanimidamide (21 mmol, 3 g) in ACN (50 ml), Et3N (21 mmol, 3.5 ml) was added at RT. The resulting mixture was heated at 80° C. and a solution of ethyl propiolate (25.1 mmol, 2.5 g) in ACN (20 ml) was added. The reaction mixture was heated at 80° C. for overnight. The solvent was evaporated and the crude was purified by flash-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (t, 3H), 3.18 (q, 2H), 4.09 (q, 2H), 5.44 (d, 1H), 6.78 (bs, 2H), 7.70 (d, 1H). LC-MS: [M−1]=239.17.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(Cc2cccc(Br)n2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5cccc(F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-fluoro-benzyl)-pyridine.
Reaction SMILES: CO[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)=O>O1CCCC1>[CH3:3][NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Solvent: C1CCOC1
Product: CNc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
3.59 gram (6.81 mmol) of (−)-2-methoxycarbonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-2b-1)) was dissolved in 170 ml of tetrahydrofuran, under the flow of nitrogen. To the solution, 27.2 ml of tetrahydrofuran solution (2M) of borane-dimethyl sulfide complex was added at 0° C. over 30 minutes and the resultant mixture was stirred for 18 hours at 88 ° C. The resultant reaction solution was extracted with 300 ml of ethyl acetate, and the extract was washed with 100 ml of saturated aqueous solution of ammonium chloride and 100 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. To the residue, 272 ml of diethylamine was added and stirred at room temperature for 30 minutes. After evaporating diethylamine, the residue was purified using a silica gel column chromatography (eluent: 1:16 mixture of ethyl acetate and hexane) to obtain 3.05 gram of the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:13])[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C>CN(C=O)C>[F:13][C:5]1[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=1
Reactant: [C-]#N
Reactant: Fc1cc(CCl)cc2c1OCCO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, 4.55 mmol) and potassium cyanide (1.55 g, 23.8 mmol) in DMF (10 mL) was stirred at 60° C. for 18 h. After cooling to rt ethyl acetate (100 mL) was added and the mixture was washed with water (2×30 mL) then brine (30 mL) and dried over sodium sulfate. Filtration and concentration followed by column chromatography on silica (4:1 hexanes/ethyl acetate) afforded (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.42 g, 46% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.61 (m, 2H), 4.30 (s, 4H), 3.62 (s, 2H)
Reaction SMILES: [N+:1]([C:4]1([CH2:10][CH2:11][C:12]2[S:13][C:14]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:15]=3[N:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-])=O.O.S(=O)(=O)(O)O.Cl>CO.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Fe]>[NH2:1][C:4]1([CH2:10][CH2:11][C:12]2[S:13][C:14]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:15]=3[N:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=[N+]([O-])C1(CCc2nc3c(s2)Cc2ccccc2-3)CCCCC1
Agent: [Fe+2]
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: NC1(CCc2nc3c(s2)Cc2ccccc2-3)CCCCC1
Yield: 14.5 %

Procedure:
To a solution of 910 mg of 2-[2-(1-nitrocyclohexyl)ethyl]-8H-indeno[1,2-d]thiazole in 10 ml of methanol were added 390 mg of iron(II) sulfate heptahydrate, 290 mg of iron reduced, 30 ml of water, and 1.5 g of concentrated sulfuric acid successively, followed by heating under reflux for 2 hours. The reaction mixture was poured into 1N hydrochloric acid, followed by extraction with ethyl acetate to remove unreacted starting materials. The aqueous layer was then neutralized, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, whereby 120 mg of yellow 2-[2-(1-aminocyclohexyl)ethyl]-8H-indeno[1,2-d]thiazole was obtained as a free base. Fumaric acid was added to the resulting compound in ethanol to cause crystallization, and the crystals were recrystallized to give a fumarate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8](O)=O.Cl.C(N(CC)CCCN=C=NCC)C.[NH2:28][C:29]1[C:30](=[O:41])[N:31]([CH2:39][CH3:40])[C:32](=[O:38])[N:33]([CH2:36][CH3:37])[C:34]=1[NH2:35].[OH-].[Na+]>C(Cl)(Cl)Cl.O.O1CCOCC1>[CH2:39]([N:31]1[C:30](=[O:41])[C:29]2[NH:28][C:8](/[CH:7]=[CH:6]/[C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:35][C:34]=2[N:33]([CH2:36][CH3:37])[C:32]1=[O:38])[CH3:40]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
3-Methoxycinnamic acid (2.48 g, 13.9 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimide hydrochloride (3.62 g, 18.9 mmol) were added to a mixture of dioxane (80 ml) and water (40 ml) containing 5,6-diamino-1,3-diethyluracil [J. Am. Chem. Soc., 75, 114 (1953)] (2.5 g, 12.6 mmol). The resulting solution was stirred at room temperature for 2 hours at pH 5.5. After a 4N aqueous solution of sodium hydroxide was added thereto to adjust the pH to >14, 40 ml of water was added and the mixture was heated under reflux for 20 minutes. After cooling, the mixture was neutralized and 50 ml of chloroform was added thereto. The organic layer was separated and the aqueous layer was extracted twice with 50 ml of chloroform. The combined extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from dimethylformamide/water to give 2.10 g (yield 49%) of Compound r as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:21][C:22]1[C:23]2[N:24]=[CH:25][N:26]([C:35]=2[N:36]=[CH:37][N:38]=1)[C@@H:27]1[O:34][C@H:31]([CH2:32][OH:33])[C@@H:29]([OH:30])[CH2:28]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:33][CH2:32][C@H:31]2[O:34][C@@H:27]([N:26]3[C:35]4[N:36]=[CH:37][N:38]=[C:22]([NH:21][C:13](=[O:20])[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:23]=4[N:24]=[CH:25]3)[CH2:28][C@@H:29]2[OH:30])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1)c1ccccc1

Procedure:
The synthesis of this product is carried out by reacting 1 eq of p-nitrobenzoyl chloride with 6-N-benzoyldeoxyadenosine for 4 hours in pyridine. After hydrolysis of the excess reagent, partial evaporation of the pyridine, extraction and evaporation of the chloroformic phase, the product is obtained by column chromatography (elution 4% methanol).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:31][CH2:32]C)([O:28][CH2:29]C)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:32][O:31][C:24]1([O:28][CH3:29])[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Yield: 99.1 %

Procedure:
A mixture of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.5 g, 1.6 mmol), triethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (20 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled, was partitioned between aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.57 g, 99%).
Reaction SMILES: C([NH:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][O:19][CH3:20])=[CH:6][N:5]=1)=O.C[O-].[Na+]>CO>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][O:19][CH3:20])=[CH:6][N:5]=1
Reactant: COCOCCCOn1cnc2cnc(NC=O)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCOCCCOn1cnc2cnc(N)nc21
Yield: 55.6 %

Procedure:
A solution of 2-formamido-9-[3-(methoxymethoxy)propoxy]purine (0.4 g, 1.42 mmol) in methanol (15 ml) was treated with sodium methoxide solution (0.5M, 5 ml) and heated to reflux for 2 hr. The cooled reaction mixture was neutralised with AMBERLITE IR 120H resin, filtered and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 ml), washed with water (2×20 ml), dried (MgSO4), filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate, followed by crystallisation from acetone/hexane to give the title compound as colourless crystals (0.2 g, 55%) mp 80°-1° C. λmax (MeOH) 223 (ε26,375), 245 (5020) and 310 nm (7320); νmax (KBr) 3320, 3180, 3080, 2940, 2880, 1645, 1610, 1580, 1505, 1465, and 1430 cm-1 ; δH [(CD3)2SO] 1.95 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.25 (3H, s, OCH3), 3.63 (2H, t, J=6.3 Hz, CH2OCH2OCH3), 4.40 (2H, t, J=6.3 Hz, CH2ON), 4.57 (2H, s, OCH2O), 6.68 (2H, br.s, D2O exchangeable NH2), 8.3 (1H, s, 8-H), 8.59 (1H, s, 6-H). (Found: C, 47.34, H 6.08% C10H15N5O3 requires: C, 47.42; H, 59.7%).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1>CN(C=O)C>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)=[CH:7][C:8]=2[O:13][CH3:14])[N:17]=1
Reactant: Fc1cccc(F)n1
Reactant: COc1cc(CCO)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(CCOc2cccc(F)n2)ccc1Oc1cccc(F)n1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To a suspension of KOH (2 mmol; 112 mg) in anhydrous DMF (1 mL) under argon, was added 4-(2-hydroxyethyl)-2-methoxyphenol (1 mmol; 168 mg) followed by 2,6-Difluoropyridine (1 mmol; 0.1 ml). The reaction mixture was stirred at 110° C. for 20 h.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]#[CH:30].CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]#[CH:30])[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: C#CCNC
Solvent: O
Solvent: CC#N
Product: C#CCN(C)c1cc(NC)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-propargylamine (79 μL, 0.95 mmol) and MeCN (10 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][CH2:36][C:37]1C=CC=[CH:39][C:38]=1OC.Cl>>[ClH:35].[CH3:28][O:27][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: COc1ccccc1CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccccc1CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Yield: 76.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-2-methoxybenzene (0.023 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(2-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (63.3 mg, 77.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.79 (d, 1H), 7.57 (m, 2H), 7.49 (d, 1H), 7.45-7.33 (m, 3H), 7.23 (m, 1H), 6.98 (m, 2H), 6.79 (m, 2H), 5.28 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H), 2.29 (s, 3H); Mass spectrum (apci) m/z=450.0 (100), 359.0 (45), 238.0 (40).
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:35]([NH2:37])[CH3:36]>C(Cl)Cl.[Pd]>[C:1]([C:5]1[C:9]([CH2:10][NH:37][CH2:35][CH3:36])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)cc1C=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(C)(C)C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
2-(2-(3-Tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.66 g, 3.84 mmol) was dissolved in DCM (40 mL) and acetic acid (20.98 g, 20 mL, 349 mmol). Ethylamine (2M in THF, 7.68 mL, 15.35 mmol) was added and the mixture was stirred for 90 min. A slurry of palladium on charcoal (10%, 1.51 g, 1.420 mmol) in DCM (30 mL) was added and the mixture hydrogenated at 4 barr for 72 h at 20° C. The catalyst was filtered through dicalite and the dicalite washed with water, DCM and MeOH. All volatiles were removed under reduced pressure and the aqueous residue was basified to pH 8 using sodium bicarbonate. The crude product was extracted with EtOAc. The organics were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography (DCM, 0-30% MeOH/DCM and 0-20% 7 N NH3 in MeOH/DCM). Concentration in vacuo yielded a white solid (800 mg, 1.73 mmol, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=1I)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=CC=C2C=1N=CC=C2NCCN(C)C)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:10]3[C:9](=[C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:13]4=[N:12][CH:11]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3c([N+](=O)[O-])cccc23)c1OC
Agent: CN(C)CCNc1ccnc2c([N+](=O)[O-])cccc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cccc([N+](=O)[O-])c4ncc3c2cc1OC
Yield: 85 %

Procedure:
N-(8-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8a). Oxalyl chloride (762 mg, 6.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (570 mg, 1.85 mmol) in anhydrous methylene chloride (20 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7a (400 mg, 1.54 mmol) and triethylamine (1.14 g, 11.3 mmol) in methylene chloride (20 mL), and the resulting mixture was stirred at reflux overnight. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 722 mg of the amide, in 85% yield; 1H NMR (CDCl3) δ 2.30 (s, 6H), 2.69 (m, 2H), 3.32 (s, 3H), 3.74 (s, 3H), 3.95 (m, 1H), 4.57 (m, 1H), 6.41 (s, 1H), 7.02 (s, 1H), 7.75 (m, 2H), 8.05 (d, 1H, J=6.6), 8.44 (d, 1H, J=8.4), 8.95 (d, 1H, J=4.4); 13C NMR (CDCl3) δ 45.4, 47.3, 55.7, 56.1, 56.5, 82.7, 110.7, 121.9, 123.3, 124.0, 126.1, 126.9, 127.2, 133.1, 140.9, 147.4, 148.4, 149.0, 150.1, 153.0, 169.9; IR (CHCl3) 1362, 1536, 1655.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([N:11]=[C:12]=[S:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:11][C:12]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[S:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)c1ccc(C(=O)N=C=S)cc1
Product: CC(C)(C)c1ccc(CNC(=S)NCC(F)(F)F)cc1
Yield: 105.2 %

Procedure:
10.82 g of 4-t-butylbenzoyl isothiocyanate obtawined in (1) and 7.54 g of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetawte. The solution was left to stand at room temperature for 24 houirs. Ethyl acetate was evaporated under reduced prerssure. The resultilng oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (4:1)) to give 15.80 g of the desired 1-(4-t-butylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea.
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Br[CH2:31][CH2:32][OH:33]>C(O)(C)C.C(O)=O>[OH:33][CH2:32][CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: OCCBr
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CC(C)O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and 2-bromo-ethanol (12.5 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzylamide (5.4 mg) as a colourless lyophilisate. LC-MS: tR=1.00 min, [M+1]+=400.26.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:26][CH2:27]1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Reactant: O=S1(=O)CCNCC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)N1CCS(=O)(=O)CC1
Yield: 72 %

Procedure:
As described for example 44, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol) was converted, using thiomorpholine 1,1-dioxide instead of 4-amino-tetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 195 mg, 72%) which was obtained as a colourless crystalline solid. MS: m/e=443.2 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=[C:6]1[C:13](OCC)=[O:14].[Cl-].[Li+].[BH4-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>COCCOC>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=[C:6]1[CH2:13][OH:14]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1Cc1c(Cl)cccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOC
Product: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1200 mg (3.5 mmol) of the compound from Example 33A together with 15 mg (0.35 mmol) of lithium chloride were dissolved in 53 ml 1,2-dimethoxyethane, and 198 mg (5.23 mmol) of sodium borohydride were added at 0° C. The mixture was stirred at RT for 1 h. For work-up, 25 ml of a saturated potassium sodium tartrate solution were added with ice cooling and the mixture was extracted with 50 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:1). This gave 800 mg (76% of theory) of the target compound.