Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31]([NH:38][CH2:39][C:40](O)=[O:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:40](=[O:41])[CH2:39][NH:38][C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:11]3)[CH2:9][N:8]([C:15](=[O:16])[NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 12 h
Yield: 39.7 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (40 mg, 0.097 mmol) obtained in Example 2 was dissolved in methylene chloride (1.0 mL). Thereafter, triethylamine (27.0 μL, 0.194 mmol), N-Boc glycine (20 mg, 0.116 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (22 mg, 0.116 mmol) were added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 12 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The resultant was dried over anhydrous sodium sulfate and was then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (22.0 mg, 40%) in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][N:32](CC3C=CC(OC)=CC=3)[CH:33]=2)=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][NH:32][CH:33]=2)=[CH:24][CH:25]=1.[CH2:11]([O:10][C:9](=[O:19])[NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=1)[C:13]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5C[C@H](Cn6ccnn6)OC5=O)cc4F)cc3)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(F)c1)OCc1ccccc1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(CNCc3c[nH]nn3)cc2)c(F)c1
Temperature: 67.5 °C
Reaction time: 12 h

Procedure:
A solution of the crude regioisomeric mixture of (5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (SC-167-71, 0.30 g, 0.528 mmol) in trifluoroacetic acid (TFA, 10 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo. The residual solids were then heated with ethyl acetate (EtOAc, 10 mL) and H2O (15 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×20 mL) and H2O (2×20 mL), and dried in vacuo at 40-45° C. to afford the crude, (5R)-3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (Compound 2 as the free base, 0.18 g, 0.24 g theoretical, 75%) as off-white powders, which by HPLC/MS and 1H NMR was found to be one pure regioisomer. For Compound 2 as the free base: 1H NMR (300 MHz, DMSO-d6) δ 3.71-3.77 (two br. s, 4H, Ar1CH2NHCH2Ar2), 3.93-3.98 (m, 1H), 4.26-4.32 (t, 1H), 4.86 and 4.87 (d, 2H), 5.14-5.22 (m, 1H), 7.35-7.59 (m, 7H, aromatic-H), 7.74 and 7.78 (s, 2H, triazole-CH), 8.19 (s, 1H, triazole-CH); C22H21FN8O2, LCMS (EI) m/e 449(M++H) and 471 (M++Na).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:4]=2[C:3]=1[F:24].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C>[CH3:25][N:26]([CH3:31])[S:27]([N:12]1[C:5]2[C:6]3[O:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([F:1])=[C:3]([F:24])[C:4]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:13]1=[O:23])(=[O:29])=[O:28]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Agent: CN(C)c1ccncc1
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)N(C)C)c(=O)n3-c1ccc(I)cc1F
Yield: 61 %

Procedure:
Intermediate I-23a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-18a: 80 mg, 0.178 mmol), N,N-dimethylaminosulfonyl chloride (38.5 mg, 0.269 mmol), TEA (54.5 mg, 0.534 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford the 60 mg of the product (61.2% yield). H1NMR (CDCl3, 300 MHz): δ 7.70-7.64 (m, 2H), 7.30-7.22 (m, 1H), 3.20 (s, 6H), 2.72 (s, 3H). LCMS: 70.3%, m/z=552.9 (M+1). HPLC: 81.3%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].N1([CH:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:27][C:28](=[O:30])[O-:29])C=CC=N1>>[C:34]([O:33][C:32]([NH:31][C:26](=[N:27][C:28](=[O:30])[O:29][C:5]([CH3:6])([CH3:20])[CH3:4])[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([CH2:8][CH2:9][C:10]([OH:17])([CH2:11][CH2:12][CH3:13])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Reactant: CCCC(O)(CCC)CCc1cccc(CCCN)c1
Product: CCCC(O)(CCC)CCc1cccc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate following the method described in Example 168 gives tert-butyl (tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamate.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1.C(OCC)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1ccc(CCl)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
In a dry flask were placed in succession 5 mL of diethyl ether, 1.21 g (0.0102 mole) of thionyl chloride, and one drop of pyridine. A solution of 1.85 g (0.0085 mole) of (4-fluoro-3-phenoxyphenyl)methyl alcohol in 5 mL of diethyl ether was added dropwise to the reaction mixture. Upon completion of addition, the reaction mixture was heated at reflux for one hour. After being cooled to room temperature, 10 mL of water was added slowly to the reaction mixture. The phases were separated. Twice the aqueous phase was extracted with 15 mL of diethyl ether, and these extracts were combined with the organic phase. The latter was washed successively twice with 10 mL of a saturated aqueous solution of sodium chloride, once with 10 mL of an aqueous solution of sodium bicarbonate, and twice with the saturated aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate and being filtered, the solvent was evaporated under reduced pressure, leaving 1.85 g of (4-fluoro-3-phenoxyphenyl)methyl chloride as a light yellow liquid. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:14]([N+:16]([O-])=O)[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O.C(O)C>O1CCCC1.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[C:14]([NH2:16])[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Br)c1)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)sc1Sc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 351D (1 equiv), iron powder (5 equiv) and ammonium chloride (3 equiv) in a mixture of tetrahydrofuran, water and ethanol was heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered through a pad of celite, which was washed with ethanol and the resultant filtrate concentrated under vacuum. The material was then dissolved in water and extracted with ethyl acetate, the organic layer dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[CH:4][C:3]=1[O:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32].[NH2:34][C:35]1([C:44]([OH:46])=[O:45])[CH:40]2[CH2:41][CH2:42][CH2:43][CH:36]1[CH2:37][CH2:38][CH2:39]2>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:34][C:35]3([C:44]([OH:46])=[O:45])[CH:40]4[CH2:41][CH2:42][CH2:43][CH:36]3[CH2:37][CH2:38][CH2:39]4)=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[CH:4][C:3]=1[O:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32]
Reactant: NC1(C(=O)O)C2CCCC1CCC2
Reactant: COc1cccc(OC)c1-c1ccc(C(=O)O)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: COc1cccc(OC)c1-c1ccc(C(=O)NC2(C(=O)O)C3CCCC2CCC3)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Yield: 77 %

Procedure:
According to the method described in example 1.8, starting from 400 mg (0.85 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid and 218 mg (1.19 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid and after reverse-phase purification and lyophilization, we obtain 220 mg of 9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of (S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.72 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:12][C:13]([C:15]1[C:16](=[O:30])[N:17]([CH3:29])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([N:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][CH:19]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([C:15]1[C:16](=[O:30])[N:17]([CH3:29])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([N:26]([CH3:27])[CH3:28])[CH:21]=[CH:20][CH:19]=2)=[O:12])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)c1c(O)c2c(N(C)C)cccc2n(C)c1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=O)c1c(O)c2c(N(C)C)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
N-Ethylaniline (4.4 g, 0.036 mol) was dissolved in 80 ml of toluene. About 30 ml of the solvent was distilled off in order to obtain a dry solution. 1,2-Dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (3.5 g, 0.012 mol) was added to the boiling solution. The ethanol formed during the reaction was distilled off together with some toluene for about 10 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (3.1 g), yield 71%.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:11]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4cccc(Cl)c4)c3)c2C)C1
Yield: 56 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 3-chlorophenylboronic acid gave [5-(3′-chloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 56% yield as light brown oil. MS: 451.0 (MH+, 1 Cl).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:15][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: BrCCCBr
Reactant: COc1ccc(Br)c(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1OCCCO2
Temperature: 110 °C
Reaction time: 12 h

Procedure:
3-bromo-6-methoxycatechol (31 g) was dissolved in DMF (50 ml), mixed with 1,3-dibromopropane (36 ml) and potassium fluoride (42 g), stirred for 12 hours while heating at 110° C. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed with an aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give Compound IIbr-a (6.7 g, 18%) as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:13])/[CH:11]=[CH:10]\[C:9]([OH:14])=[O:15]
Reactant: O=C1C=CC(=O)O1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: O=C(O)/C=C\C(=O)OCc1ccccc1

Procedure:
Poly(styrene [50 mol %], benzyl hydrogen maleate [50 mol %]) was prepared by stirring at reflux for 25 hours a mixture of poly(styrene [50 mol %], maleic anhydride [50 mol %]), 200 mL of benzyl alcohol and 400 mL of THF. The THF was removed on a rotary evaporator, and the product was precipitated in hexane followed by precipitation from THF with diethyl ether to give 46 g of poly(styrene, benzyl hydrogen maleate). A mixture of 25 g of poly(styrene, benzyl hydrogen maleate), 150 mL of 3,4-dihydro-2H-pyran, and 0.5 g of pyridine hydrochloride was stirred at reflux 18 hours. THF was added to reduce the viscosity, and the mixture was stirred 1 hour with crosslinked poly(dimethylaminomethylstyrene). After filtration, the product was precipitated from the filtrate in methanol to give 29 g of poly(styrene, benzyl maleate, tetrahydropyranyl maleate). 1H HMR (360 MHz) shows the molar ratio of tetrahydropyranyl groups (δ 5.8 ppm) to benzyloxy groups (δ 5.0 ppm) to be about 4.4:1. Titration with 0.1N sodium hydroxide shows 0.09 meq/g of COOH groups. DSC: decomposition endotherm 140.75° C. TGA: 24.7% weight loss at 147.9° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClCCl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3s2)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (7.0 g) and 2-chlorobenzthiazole (5.26 g) were dissolved in dichloromethane to ensure good mixing. The solvent was then evaporated and the residue fused at 130° C. for 16 hours. The cooled reaction mixture was subjected to chromatography on silica (chloroform:methanol 10:1) to give the title compound as an oil (8.5 g). This was treated with maleic acid in isopropanol to give 2-[3-[3- [3-(piperidinomethyl)phenoxy]propylamino]benzthiazole dimaleate, m.p. 113° C. (decomp) (recrystallised from ethylacetate and isopropanol-ethyl acetate).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=2)[CH2:9]1.[Cl-].[Cl-].[Ca+2]>O1CCCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][CH2:6][NH:5][C:2]([NH:1][CH3:4])=[O:3])[CH2:9]2)=[CH:21][CH:22]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Reactant: CN=C=O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CNC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A mixture of 0.9 parts of isocyanatomethane, 5.3 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 63 parts of tetrahydrofuran was stirred for 1.5 hour at room temperature using a CaCl2 -tube. Another portion of 0.9 parts of isocyanatomethane was added and stirring was continued for 1.5 hour at room temperature. The precipitated product was filtered off, washed with tetrahydrofuran and dried in vacuo at room temperature, yielding 5.0 parts (81%) of N-[2-[3-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-pyrrolidinyl]ethyl]-N'-methylurea; mp. 161.1° C. (compound 188).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C(C)(C)C)=[O:14])=[N:11][CH:12]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cnccn2)cn1
Reaction time: 10 h

Procedure:
To a solution of tert-butyl 5-(pyrazin-2-yl)picolinate 41-3 (1.11 g, 4.32 mmol) in dichloromethane (4.5 mL) was added TFA (4.5 mL) dropwise at room temperature. The mixture was stirred for 10 hours, and then the solvents were removed by rotary evaporation. The resulting pale yellow oil was further dried under lyophilizer to afford 5-(pyrazin-2-yl)picolinic acid 41-4 in TFA salt as a pale yellow solid. MS m/z 202.1 (M+1)
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][C:18]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([O:30]C(CC(C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43].[Li][Al](OC)OC>O.O1CCCC1.C(O)=O>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(OC(=O)CC(C)C)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: [Li][Al](OC)OC
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -50 °C

Procedure:
This example describes reduction of ansamitocins with LiAl(OMe)2.5H1.5 using water followed by aqueous formic acid quench. Ansamitocins (1.0 g, 1.57 mmol) were weighed into a three necked flask equipped with a thermometer. Tetrahydrofuran (5 mL) was added to the flask with stirring, and the flask was cooled in a −50° C. cooling bath. Once the contents of the flask reached −35° C., a solution of 0.67 M LiAl(OMe)3H in tetrahydrofuran (18.5 mL, 12.4 mmol) was added dropwise by syringe using a syringe pump. The temperature of the reaction was maintained between −30° C. and −40° C. throughout the addition. After addition was complete the reaction was stirred for 2 hours at between −32° C. and −37° C. Deionized water (2.5 mL) was added dropwise to the −35° C. reaction to give a basic quenched mixture. The basic quenched mixture was analyzed by the thin layer chromatography assay described in example 6. The compound of Formula (I) was detected. After 30 min the basic quenched mixture was analyzed again by the thin layer chromatography method. The compound of Formula (I) was no longer detected. Aqueous formic acid (deionized water, 5 mL, and 88% formic acid, 0.62 mL) was then added to the flask followed by 22 mL of ethyl acetate. The cooling unit was turned off and the mixture was allowed to slowly warm to room temperature. The pH of the mixture was checked with pH paper and found to be approximately pH 6. The mixture was vacuum filtered, and solvent was removed by rotary evaporation under vacuum. Butyl acetate (5 mL) was added to the residue, the solvent was then evaporated to remove any remaining water. The residue was purified by silica chromatography using a mobile phase of dichloromethane:methanol 95:5 (v:v) to give 0.63 g of maytansinol (71% yield by weight).