Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccc(F)cc5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 286. NMR (DMSO): 2.55-2.58 (4H, m), 2.98-3.03 (4H, m), 3.73-3.77 (4H, m), 3.88 (2H, s), 3.90-3.94 (4H, m), 7.06 (2H, br. s), 7.32 (1H, s), 7.50-7.55 (2H, t), 7.80-7.84 (2H, m), 9.10 (2H, s). MS (ESI+): MH+ 570.23 (100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
Reaction of 3-bromo-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (95% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12 (1H, m, aromatics), 7.48 (1H, m, aromatic), 7.82 (1H, m, aromatic), 7.97 (1H, s, CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(F)cc2)cc1
Yield: 89 %

Procedure:
From 4-fluoro-bromobenzene and 4-methoxyphenyl boronic acid, yield 89%; mp 92-94° C. (lit.,2 94-96° C.); IR: 1504, 1276 and 1041; 1H NMR (400 MHz; CDCl3): 7.53-7.46 (4H, m), 7.11 (2H, t, J 8.7), 6.98 (2H, d, J 8.8) and 3.85 (3H, s); m/z (EI) 202 (95%, M+), 159 (100), 133 (90) and 69 (40)(Found: M+, 202.079. C13H11FO requires M, 202.079).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[N:3][N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2cnn(O)c2)cc1
Product: COc1ccc(-c2cnn(OC(=O)N(C)c3ccccc3)c2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-4-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (6%, oil).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12](O)[CH3:13])=[N:10][CH:11]=2)=[CH:2]1.P(Br)(Br)[Br:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-]>[Br:16][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:11][N:10]=1)[CH3:13]
Reactant: CC(O)c1ccc(-c2ccoc2)cn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(-c2ccoc2)cn1
Temperature: 2.5 °C
Yield: 73.8 %

Procedure:
To a solution of 1-(5-(furan-3-yl)pyridin-2-yl)ethanol (0.075 g, 0.403 mmol) in chloroform (5 ml) was added PBr3 (0.321 g, 1.209 mmol), at 0-5° C., the reaction maintained at the same temperature for 15 min, the reaction was slowly warmed to rt and was maintained at rt for another 2 h. The contents were diluted with ethyl acetate (100 mL), bicarbonate solution (10 mL) was added, the organic layer was separated, the organic layer dried over sodium sulphate and distilled to provide 2-(1-bromoethyl)-5-(furan-3-yl)pyridine (0.075 g, 75% yield). LC-MS m/z calcd for [M+H]+ 253.99. found 254.0.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.[I:17]I>C1COCC1.CCOC(C)=O>[F:9][C:10]1[C:15]([I:17])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: II
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(I)c(F)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium diisopropylamide (4.34 mL, 8.69 mmol, 2.0 M solution in heptane/THF/ethylbenzene) in THF (20 mL) at −78° C. under a nitrogen atmosphere was added 2,6-difluoropyridine (0.79 mL, 8.69 mmol). The mixture was stirred at −78° C. for 45 min before iodine (2.21 g, 8.69 mmol) in THF (10 mL) was added via syringe. The reaction was stirred for an additional 30 min at −78° C. The reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium sulfite. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give 2,6-difluoro-3-iodopyridine.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 85 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-ethyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (33 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (br s, 3H), 8.30 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.54-7.38 (m, 7H), 7.32 (d, J=8.3 Hz, 2H), 4.77 (q, J=7.2 Hz, 2H), 2.62-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.86-1.75 (m, 1H), 1.47 (t, J=7.2 Hz, 3H). LCMS (Method E): RT=3.58 min, [M+H]+=436.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C1COCC1>[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:15][CH2:16][N:17]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:19]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(N2CCNCC2)c(C(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N1CCN(c2ccc(C)cc2C(C)(C)C)CC1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
To a stirred suspension of 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (Reference Example 10, 0.300 g, 0.98 mmol) and triethylamine (548 μl, 3.93 mmol) in THF (10 mL) stirring at 0° C. was added ethyl chloro(oxo)acetate (0.175 mg, 1.28 mmol). The mixture was warmed to room temperature. After 3 days the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide ethyl [4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl](oxo)acetate (0.233 g, 71%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc(Br)cc2ccccc12
Reactant: COC(=O)c1ccc(C)c(N)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)cc3ccccc23)c1C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of 3-bromo-1-naphthoic acid (0.40 g, 1.59 mmol) in CH2Cl2 (8 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (0.26 g, 1.43 mmol, see preparation 10) and triethylamine (0.78 ml, 5.38 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.03 ml, 3.18 mmol) is added via syringe and stirred at room temperature. After 16 hours, the reaction is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) with 5% EtOAc in hexane as eluent to afford the product as a white solid (0.52 g, 79%). Mass spectrum (m/z): 412.3 (M+1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C[N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[CH3:37])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: C[C@H]1CCCN1C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.3 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (600 mg, 1.348 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and (2S)-1,2-dimethylpyrrolidine (1.37 mL, 13.483 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.858 g, 13.483 mmol). The reaction was stirred at room temperature overnight then purified by SFC. This compound was separated by RTP CASS Group. The fraction of enantiomer #1 is 99.7% chirally pure to give 119.9 mg of the title compound (17.3%).
Reaction SMILES: NC1C=CC=CN=1.BrC(C=O)C=O.[N:14]1[CH:15]=[C:16]([CH:23]=O)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12.C(N(CC)CC)C.Cl.[NH2:33][CH2:34][CH:35]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:36][C:37](OC)=[O:38]>C(O)C.O1CCOCC1>[N:14]1[CH:15]=[C:16]([CH2:23][N:33]2[CH2:34][CH:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:36][C:37]2=[O:38])[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: COC(=O)CC(CN)c1ccccc1
Reactant: O=Cc1cnc2ccccn12
Agent: Cl
Agent: Nc1ccccn1
Agent: O=CC(Br)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CC(c2ccccc2)CN1Cc1cnc2ccccn12
Temperature: 25 °C

Procedure:
A solution of 2-aminopyridine x8 (1 g, 1 eq, 10.6 mmol) and bromomalonaldehyde x9 (1.6 g, 1 eq, 10.6 mmol) in 1.4 dioxane (20 ml) is refluxed for 3 days (Imidazo[1,2-a]pyridine-3-carbaldehyde x10 is formed in situ and not isolated). After cooling to room temperature, triethylamine (2.96 ml, 2 eq, 21.25 mmol), methyl 4-amino-3-phenylbutanoate hydrochloride x11 (2.44 g, 1 eq, 10.6 mmol) and ethanol (10 ml) are successively added. The mixture is then allowed to react during 3 days at room temperature. The reaction mixture is poured on ice, and organic solvents are removed under reduced pressure. The resulting aqueous layer is extracted by CH2Cl2 and the cumulated organic layers are dried over MgSO4, filtered, and condensed under reduced pressure. The crude product is purified by preparative chromatography on silicagel (CH2Cl2/iPrOH: 97/3 (v/v)), then recristaltized in ethyl acetate leading to 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one 7 as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:29](=[O:28])[C:24]5=[CH:23][C:22]([O:21][CH3:20])=[CH:32][CH:31]=[C:25]5[C:26]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-methoxyphthalic anhydride (1.78 g, 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide.
Reaction SMILES: [CH2:1]([Cl:3])Cl.Cl[C:5]1[CH:6]=[C:7]([C@@H:11]([O:14][C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[CH2:12][OH:13])[CH:8]=[CH:9]C=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(N(CC)CC)C>[CH3:20][S:21]([O:13][CH2:12][C@@H:11]([C:7]1[CH:8]=[CH:9][C:1]([Cl:3])=[CH:5][CH:6]=1)[O:14][C:15]([O:18][CH3:19])([CH3:17])[CH3:16])(=[O:23])=[O:22]
Reactant: COC(C)(C)O[C@@H](CO)c1cccc(Cl)c1
Reactant: ClCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(C)(C)O[C@@H](COS(C)(=O)=O)c1ccc(Cl)cc1

Procedure:
Into methylene chloride (20 ml) were added (R)-2-(3-chlorophenyl)-2-(1-methoxy-1-methylethyloxy)ethanol obtained in 3) above (5.0 g) and triethylamine (3.9 g) and further, under ice-cooling and dropwise, methanesulfonyl chloride (2.46 g), and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off to obtain a colorless oily compound mentioned above (6.33 g, 96.0%). The optical purity of the product obtained was 99.9% e.e.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=1.C(OC)=O.[NH2:21][C:22]([NH2:24])=[S:23].[CH2:25](N(CC)CC)C>COCCOC>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][C:6]2[C:5](=[O:16])[NH:21][C:22](=[S:23])[NH:24][CH:25]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)CCc1ccnc(OC)c1
Reactant: NC(N)=S
Reactant: CCN(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: COC=O
Solvent: COCCOC
Product: COc1cc(Cc2c[nH]c(=S)[nH]c2=O)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a suspension of NaH, 60% dispersion on mineral oil (1.3 eq, 320 mg, 60%) in 1.5 ml of dry 1,2-dimethoxyethane under argon atmosphere was added a solution of 3-(2-methoxy-pyridin-4-yl)-propionic acid methyl ester (1.2 g, 6.14 mmol, 1 eq) and methyl formate (2 eq, 760 μl) in 8 ml of dry 1,2-dimethoxyethane. The sealed mixture was stirred at room temperature for 16 hours (overnight). Solvent from the mixture was then evaporated. In the rest was added 15 ml of diethyl ether and using ultrasound bath the precipitate was formed. Mother liquor was removed and in the rest was triturated once more with diethyl ether. The precipitate was dried and was dissolved in 10 ml of absolute ethanol, thiourea (1.5 eq, 700 mg) and triethylamine (1.1 eq, 936 μl) were added and the resulting mixture was heated at 90° C. (temperature on display of heating device) for 2 hours. The solvent was evaporated and the rest was dissolved in 10 ml of water. pH of the solution was adjusted to 6-7 and the formed precipitate was collected by filtration and was dried to 5-(2-methoxy-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (900 mg, yield=58.7%, purity=95%). MS: [M+H]+=250.15 1H NMR (300 MHz; DMSO-d6) δ/ppm 3.51 (s, 2H), 3.81 (s, 3H), 6.65 (s, 1H), 6.85 (dd, J=5.42 Hz, J=1.03 Hz 1H), 7.42 (s, 1H), 8.03 (d, J=5.42 Hz, 1H), 12.02-12.76 (m, 2H)
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].N12CCCN=C1CCCCC2.Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C1C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[CH3:8]
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)CC(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a 5° C. solution containing 27.8 g (246 mmol) of ethyl cyanoacetate and 38.2 g (251 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene in 420 mL of benzene was added over 30 minutes a solution of 1-bromo-2-butanone in 70 mL of benzene. The ice bath was removed and the reaction stirred for 1 hour at ambient temperature. At this time, the solids were removed by filtration and washed with 100 mL of methyl tert-butyl ether. The filtrate and the wash were combined and concentrated. The crude product was purified by short path distillation (0.2 torr, 140° C.) to provide 40.0 g (88.9%) of 2-cyano-4-oxohexanoic acid ethyl ester as a colorless oil. nmr (500 MHz, CDCl3) δ1.09 (t, J=7.3 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.96 (dd, J=5.5, 18.0 Hz, 1H), 3.16 (dd, J=7.2, 18.0 Hz, 1H), 3.96 (dd, J=5.5, 7.2 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[CH3:26][NH:27][CH2:28][C:29]#[CH:30]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([N:27]([CH2:28][C:29]#[CH:30])[CH3:26])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: C#CCNC
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: C#CCN(C)C1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3NC3CN21
Product: NC(=O)O
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 50 mg (0.14 mmol) of mitomycin A in 10 ml of anhydrous methanol was stirred with 150 mg (2 mmol) of N-methylpropargylamine at room temperature. The reaction appeared to be complete in 3 hours, as revealed by TLC. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated under reduced pressure. Recrystallization from a mixture of methylene chloride and hexane gave 20 mg (37% yield) of the desired product as purple-colored crystals having a melting point of 86°-87° C. (decomposing) and providing the following analysis:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([F:8])[C:4]([CH3:7])([OH:6])[CH3:5].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].N1C=CC=CC=1>C(Cl)Cl>[C:13]1([O:12][C:10](=[O:11])[NH:1][CH2:2][C@@H:3]([F:8])[C:4]([OH:6])([CH3:7])[CH3:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(O)[C@H](F)CN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)[C@H](F)CNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.3 %

Procedure:
To a solution of (R)-4-amino-3-fluoro-2-methylbutan-2-ol (100 mg, 0.825 mmol) in DCM (3 mL) was added phenyl chloroformate (0.124 mL, 0.990 mmol) at 0° C. followed by pyridine (0.100 mL, 1.238 mmol); the reaction mixture was stirred at RT for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with a 1.5 N aq. solution of HCl, dried over Na2SO4, filtered and the filtrate evaporated under vacuum to afford Intermediate 336A as a colorless liquid (130 mg, 65%). The crude product was used in the subsequent transformation without further purification. 1H NMR (300 MHz, chloroform-d) δ ppm 7.33-7.44 (m, 2H), 7.06-7.31 (m, 3H), 5.48 (bs, 1H), 4.30-4.56 (m, 1H), 3.73 (m, 1H), 3.33-3.51 (m, 1H), 1.91 (m, 1H), 1.32 (dd, J=11.95, 1.23 Hz, 6H).
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:19][C@H:20]4[C@H:24]5[O:25][CH2:26][C@@H:27]([OH:28])[C@H:23]5[O:22][CH2:21]4)[NH:18][C:13]3=[CH:12][C:11]=2[Cl:29])=[CH:6][CH:5]=1.[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])[CH3:31]>O1CCOCC1.O>[OH:28][C@@H:27]1[CH2:26][O:25][C@@H:24]2[C@H:20]([O:19][C:17]3[NH:18][C:13]4[C:14]([N:16]=3)=[N:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:36]5[CH:37]=[CH:38][C:33]([C:30](=[O:32])[CH3:31])=[CH:34][CH:35]=5)=[CH:5][CH:6]=3)=[C:11]([Cl:29])[CH:12]=4)[CH2:21][O:22][C@H:23]12
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2[nH]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)cc1
Temperature: 80 °C

Procedure:
LiOH (0.41 ml, 1.230 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41.8 mg, 0.051 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[[5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (225.2 mg, 0.497 mmol) and 4-acetylphenylboronic acid (100.3 mg, 0.612 mmol) in dioxane (4.0 ml) and water (0.59 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 18 h. The reaction mixture was then partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a yellow solid. The solid was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a light yellow solid. LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.10 (M+H)+ (Rt 1.14/2 min); 1H NMR δ (ppm) (CD3OD): 8.11 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.77-7.82 (m, 4H), 5.55 (qt, J=5 Hz, 1H), 4.97 (t, J=5.3 Hz, 1H), 4.47 (t, J=4.8, 1H), 4.27-4.30 (m, 1H), 4.17 (dd, J=5.8, J=10.3, 1H), 4.11 (dd, J=4.8 Hz, J=10.3, 1H), 3.90 (t, J=7.5 Hz, 1H), 3.60 (t, J=8.8 Hz, 1H) 2.65 (s, 3H).