Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6])C.[BH4-].[Na+]>CCO.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH:5]([OH:6])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(O)c1ccco1
Yield: 70 %

Procedure:
A solution of the product from step a.) (25 g, 135 mmol) in EtOH (250 ml) was cooled to 0° C. and treated with a solution of NaBH4 (2.5 g, 66 mmol) in H2O (27 ml) for 5 minutes. Next, the reaction mixture was quenched with AcOH (17 ml) and H2O (271 ml) and concentrated to dryness. The crude oil was dissolved in CH2Cl2 (300 ml), washed with brine (2×100 ml), dried (MgSO4) and concentrated providing 17.5 g (70%) of the above subtitle compound, which was carried forward without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Reactant: O=S1(=O)CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCS(=O)(=O)CC2)s1

Procedure:
2-(1,1-Dioxo-thiomorpholin-4-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and thiomorpholine-1,1-dioxide. MS calcd. for C24H21ClN4O4S2 [(M+H)+] 529.1, obsd. 529.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[CH3:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)n(-c2ccccc2)n1

Procedure:
172 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(3,4-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCS2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCCS2
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[2,3-c]pyridazine (320 mg) in 1,4-dioxane/water (20 ml/5 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 2 ml) and sodium periodate (1.08 g), initially stirred in an ice-bath, then allowed to warm to room temperature. After 2.5 hours the mixture was evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (50 g) and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a white solid (116 mg, 36%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:17]=[C:18](/[CH:20]=[C:21](\[CH3:27])/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:17]=[C:18](/[CH:20]=[C:21](\[CH3:27])/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: ClB(Cl)Cl
Product: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(O)cc2)n1
Yield: 60 %

Procedure:
According to the procedure for preparation of 4.3, ester 13.1 (167 mg, 0.376 mmol) was treated with BCl3 (1.88 mmol) to yield 80 mg (60%) of 13.3. MS (ESI) 355.3 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:29](O)([C:31]([F:34])(F)F)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:29][C:31]([F:34])=[CH:16][CH:15]=4)=[O:7])[CH2:9][CH2:10]3)=[CH:15][C:16]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Solvent: ClCCl
Product: CC(C)Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(isopropylamino)quinoline (33 mg, 0.08 mmol) is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (13 μL, 0.11 mmol) and triethylamine (80 μL, 0.57 mmol) to give a colorless solid.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(Cl)C(=O)Cl
Product: CC(Cl)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 63.5g (0.5 mole) of 2-chloropropionyl chloride with 67g (0.5 mole) of tert-butylbenzene. Obtained after high vacuum concentration was 100g of clear, yellow liquid product: ir (film) 3.4 (s), 5.9 (s), 6.3 (s), 8.0 (s), 10.5 (s), 11.8 (s) microns; nmr (CDCl3) 7.67 (4H, d of d), 5.21 (1H, q), 1.67 (3H, d), 1.28 (9H, s) ppm. A VPC analysis indicated one pure product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: N#CCCCc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: N#CCCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-butyronitrile (30 mg) in ethanol (30 mL) is hydrogenated over 10% Pd/C at 1 atm for 1 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure to give the title compound. It is converted to a potassium salt by addition of 1 equivalent of KHCO3: (M−1)−=294.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([CH3:28])[C:24]=1[C:25]([NH2:27])=[O:26]>C(N(CC)CC)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH3:28])[C:24]=3[C:25]([NH2:27])=[O:26])=[O:18])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(OCCn2ccnc2)cc1
Reactant: Cc1csc(N)c1C(N)=O
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Cc2ccc(OCCn3ccnc3)cc2)c1C(N)=O

Procedure:
This compound was prepared from 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetic acid and 2-amino-4-methylthiophene-3-carboxamide using protocol B except that triethylamine was also added. The crude product was purified via silica gel column chromatography. Method[1], MS(ESI) 385.1, Retention time=1.254 min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH2:7][CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(Cl)nc2c1NC(=O)C1COCCN21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)nc2c1NCC1COCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A round-bottom flask was charged with 2-chloro-4-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (387 mg, 1.520 mmol) in THF (7.6 mL). To the resulting suspension was added lithium aluminum hydride in THF (1.0 M, 1975 μL, 1.975 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ethyl acetate (˜1 mL) was subsequently added in portions at 0° C. Aqueous saturated NH4Cl (5 mL) was then added dropwise until bubbling stopped. The upper organic layer was decanted, concentrated, and then partitioned between brine and ethyl acetate. The murky bottom layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over MgSO4, filtered, and concentrated. The product was triturated with ether/EtOAc and filtered under N2 to give the title compound as a yellow solid (264 mg, 72%). ESI-MS m/z [M+H]+ calc'd for C10H13ClN4O, 241.08; found 241.6.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(OC([N:61]1[CH2:66][CH2:65][CH:64]([C:67]2[CH:72]=[CH:71][C:70]([NH2:73])=[C:69]([O:74][CH3:75])[CH:68]=2)[CH2:63][CH2:62]1)=O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>CN(C)C=O>[CH3:75][O:74][C:69]1[CH:68]=[C:67]([CH:64]2[CH2:63][CH2:62][NH:61][CH2:66][CH2:65]2)[CH:72]=[CH:71][C:70]=1[NH:73][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: Cc1cc(-c2ccccc2N(C)S(C)(=O)=O)n2nc(O)ncc12
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2c(C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 8-dram vial, N-[2-(2-Hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (210 mg, 0.63 mmol), N,N-Dimethylformamide (2.33 mL), N,N-Diisopropylethylamine (0.247 mL, 1.42 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.276 g, 0.773 mmol) were added. The reaction was stirred at room temperature for 30 minutes. 4-(4-Amino-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.434 g, 1.42 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The resulting solid was treated with Methylene chloride (3.50 mL, 54.6 mmol) and Trifluoroacetic Acid (1.17 mL, 15.1 mmol) and stirred at room temperature overnight. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give N-{2-[2-(2-Methoxy-4-piperidin-4-yl-phenylamino)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide a yellow solid (0.135 g, 41%). LCMS (E/I+) 521.13 (M+H). NMR 1H (DMSO-d6)-8.96 (s, 1H), 8.47-8.62 (m, 1H), 8.15-8.33 (m, 1H), 7.88-8.00 (m, 2H), 7.46-7.68 (m, 4H), 6.84 (s , 1H), 6.82 (s, 1H), 6.66 (d, 1H, J=8.11 Hz), 3.86 (s, 3H), 3.39 (d, 2H, J=12.75), 3.07 (s, 3H), 2.90-3.04 (m, 2H), 2.88 (s, 3H), 2.72-2.84 (m, 1H), 1.95 (d, 2H, J=13.48 Hz), 1.68-1.84 (m, 2H).
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(C1C=C(/C=C\C2C=CC=CC=2)C=CC=1)(=[O:28])CCCCC>>[C:16]1([CH2:15][CH2:14][CH:10]([CH2:11][CH2:12][CH3:13])[CH2:9][C:8]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:28])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCC(=O)c1cccc(/C=C/c2ccccc2)c1
Reactant: CCCCCC(=O)c1cccc(/C=C\c2ccccc2)c1
Product: CCCC(CCc1ccccc1)CC(=O)c1ccccc1

Procedure:
This compound was prepared by the catalytic reduction (H2, 10% Pd-C, ethanol) of either trans-3-hexanoyl stilbene, cis-3-hexanoyl stilbene or, 3-hexanoyl diphenyl acetylene in nearly quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7](I)[CH:6]=1)=[O:4].[CH2:20]([S:22]([C:25]1[CH:26]=[C:27](C2C3C4N=CC=NC=4NC=3C=CC=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH2:20][CH3:21])(=[O:23])=[O:24])[CH:26]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c2c(c1)[nH]c1ncc(C)cc12
Reactant: CCS(=O)(=O)c1cccc(-c2cccc3[nH]c4nccnc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from Compound 131 according to the procedure outlined in the preparation of Compound 81. MS (ES) [m+H] calc'd for C22H20N2O4S, 409; found 409.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:32]([CH3:34])[CH3:33])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]([CH3:31])[CH:19]=2)=[O:17])[N:13]=1.[H-].[Na+].[CH3:37]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:32]([CH3:33])[CH3:34])=[C:12]([CH2:14][CH:15]([CH3:37])[C:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]([CH3:31])[CH:19]=2)=[O:17])[N:13]=1
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(=O)C(C)Cc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-methylphenoxy]acetate (450 mg, 0.89 mmol) was dissolved in dry THF (4 mL). Sodium hydride (40 mg, 1.00 mmol) was gradually added to the solution. The mixture was stirred for 30 minutes at room temperature. Methyl iodide (0.07 mL, 1.12 mmol) was dropwise added to the mixture. The resulting mixture was stirred for 27 hours at room temperature. Sodium hydride (10 mg, 0.25 mmol) and methyl iodide (0.02 mL, 0.32 mmol) were further added to the mixture. The resulting mixture was stirred for 19 hours 30 minutes at room temperature. The solvent was removed under reduced pressure. Ethyl acetate (5 mL) was added to the residue. The residue was washed with a saturated saline (2 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (218 mg) as colorless oil (purity 97%, yield 29%).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C@@H:10]2[CH2:12][O:11]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(O)C.C([N:18]([CH2:21][CH3:22])CC)C>>[N:18]1([CH2:12][C@H:10]([OH:11])[CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1nccn1C[C@@H]1CO1
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C[C@@H](O)CN1CC1

Procedure:
A solution of 0.3 g (1.8 mole) of (R)-(+)-2-nitro-1-(2-oxiranylmethyl)-1H-imidazole, 0.24 g (5.4 mmole) of 1H-aziridine, and 3.5 mL of 99:1 absolute ethanol:triethylamine is heated at reflux for 10 minutes, cooled, and concentrated. The residue is crystallized from 99:1 absolute ethanol:triethylamine to give 0.22 g of product, mp 118.5°-120° C. [α]D24 =+23.5° [C0.98, chloroform].
Reaction SMILES: [Li]CCCC.[N:6]([C:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=[N+:7]=[N-:8].CON(C)[C:22](=[O:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>C1COCC1>[N:6]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=[N+:7]=[N-:8]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(Br)cc1
Reactant: CON(C)C(=O)Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(N=[N+]=[N-])c1ccc(C(=O)Cc2cccs2)cc1
Reaction time: 0.5 h

Procedure:
nBuLi (1.6M in hexane, 2.88 mL, 4.60 mmol) was added dropwise to a solution of 1-(1-azido-1-methylethyl)-4-bromobenzene (2-3, 1.03 g, 4.28 mmol) in THF (20 mL) at −78° C. After 15 min a solution of N-methoxy-N-methyl-2-thien-2-ylacetamide (1-1, 0.78 g, 4.18 mmol) in THF (1 mL) was added. After an additional 30 min at −78° C., the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to give an oil. The crude product was purified via automated flash column chromatography on silica gel (5% CH2Cl2, 0-10% EtOAc/hexanes over 30 min) to give the title compounds as a yellow oil. LRMS m/z (M+1) Calcd: 286.1,. Found 286.2.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:42]([CH3:44])[CH3:43])=[N:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:42]([CH3:44])[CH3:43])=[N:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(NC(=NS(=O)(=O)c3ccccc3)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(C)cc(NC(=NS(=O)(=O)c3ccccc3)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-ethyl-4-methyl-6-(3,3-dimethyl-2-phenylsulphonyl-guanidino) -1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][N:15]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=3[CH:4]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: O=CC1CC1
Product: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 43.4 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.085 g, 0.24 mmol) was reacted with cyclopropane carboxaldehyde (180 μL, 2.4 mmol) to give 0.042 g (43%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:3][CH2:4][CH2:5][C:6]#[N:7].CC(CC(C)=CCCC#N)C#N.CC(C=C(C)CCCC#N)C#N.CC(C=C(C)CC(C)C#N)C#N.[CH2:49]=[C:50]([CH2:56][CH2:57][CH2:58][C:59]#[N:60])[CH2:51][CH2:52][CH2:53][C:54]#[N:55].CC(CC(=C)CCCC#N)C#N.CC(CC(=C)CC(C)C#N)C#N>>[CH3:1][C:2]([CH2:3][CH2:4][CH2:5][C:6]#[N:7])=[CH:8][CH2:9][CH2:10][C:11]#[N:12].[CH2:49]=[C:50]([CH2:51][CH2:52][CH2:53][C:54]#[N:55])[CH2:56][CH:57]=[CH:58][C:59]#[N:60]
Reactant: C=C(CCCC#N)CCCC#N
Agent: C=C(CC(C)C#N)CC(C)C#N
Agent: C=C(CCCC#N)CC(C)C#N
Agent: CC(=CC(C)C#N)CC(C)C#N
Product: C=C(CC=CC#N)CCCC#N

Procedure:
The dinitrile reaction product mixture obtained by the reaction of isobutylene with acrylonitrile. This dinitrile reaction product mixture generally contains 5-methyl-4-nonenedinitrile, 2,4-dimethyl-4-octenedinitrile, 2,4-dimethyl-3-octenedinitrile, 2,4,6-trimethyl-3-heptenedinitrile, 5-methylenenonanedinitrile, 2-methyl-4-methyleneoctanedinitrile, and 2,6-dimethyl-4-methyleneheptanedinitrile. In this mixture, 5-methyl-4-nonenedinitrile and 5-methylenenonenedinitrile generally form the majority.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:15]1CC[O:18][CH2:17][CH2:16]1.C(OC(Cl)=O)C(C)C.C(CN)O>C(Cl)Cl>[OH:18][CH2:17][CH2:16][NH:15][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: NCCO
Solvent: ClCCl
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (1.734 g, 10.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (100 mL) and cooled to 0° C. in an ice bath. The flask was then charged with N-methyl morpholine (1.44 mL, 15.0 mmol) and isobutlychloroformate (1.51 mL, 11.5 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 20 min until the solution became cloudy. At which point freshly distilled ethanolamine (695 uL, 11.5 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature to form N-(2-hydroxyethyl)quinoline-2-carboxamide was formed according to the formula
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH3:14])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C([OH:17])C.O>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:17])[CH:10]([OH:9])[C:11]([CH2:13][CH3:14])=[CH2:12])[CH3:2]
Reactant: C=C(CC)C1OC=NC1C(=O)OCC
Reactant: CCO
Solvent: O
Product: C=C(CC)C(O)C(NC=O)C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manneranalogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. Thewhole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1>[C].[Pd].C(O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]2[C:9]3[C:14](=[CH:13][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1CCOCC1)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
A mixture of 2-(5,6-dihydro-2H-4-pyranyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole (83 mg), 10% palladium carbon (15 mg) and ethanol (5 ml) was stirred at 15 to 30° C. for 24 hours under hydrogen atmosphere. The mixture was filtered and the mother liquid was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=0.2:1) to obtain 40 mg of the desired product as a white crystal.