Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N12CCCN=C1CCCCC2>>[CH3:1][CH:2]([CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=CC(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)C=C(C)C
Temperature: 160 °C
Yield: 18 %

Procedure:
Ethyl 2,4-dimethyl-3-pentenoate was prepared as follows. A 25 ml flask equipped with a condenser and kept under nitrogen, was charged with 1.0 g (6.4 mmole) of ethyl 2,4-dimethyl-2-pentenoate and 0.975 g (6.4 mmole) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and the mixture was heated to 160° C. After 18 hours of reaction, followed by cooling, the reaction mixture was poured onto water and extracted with ether. The organic phase was washed successively with a 5% aqueous solution of HCI, water and brine, then dried on Na2SO4 and concentrated. After distillation on a bulb-to-bulb apparatus (80-100° C, 5.32 x 102 Pa) there were obtained 0,734 g of a 55:45 mixture of ethyl 2,4-dimethyl-2-pentenoate and ethyl 20 2,4-dimethyl-3-pentenoate. The two compounds were separated by flash-chromatography [SiO2 (30 g), cyclohexane:ethyl acetate =98:2]. 0.180 g of ethyl 2,4-dimethyl-3-pentenoate were obtained. NMR(1H): 1,19(d, J=7, 3H); 1,25(t, J=7, 3H); 1,66(d, J=1, 3H); 1,72(d, J=1, 3H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=3)[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]2[N:8]=1
Reactant: C1COCCN1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A, 81 mg, 0.228 mmol) and morpholine (67 mg, 0.761 mmol) in DMF (0.912 mL) was stirred at 100° C. for 90 min, then cooled to rt and maintained overnight. The mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (50.2 mg, 54%). 1H NMR (DMSO-d6) δ: 11.45 (s, 1H), 9.28 (d, 1H), 8.59-8.63 (m, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.31 (s, 1H), 6.21 (s, 1H), 3.80-3.89 (m, 4H), 3.68-3.80 (m, 4H), 2.39 (s, 3H); ESI-MS: m/z 407.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC(OP(O[NH2:29])(OC2C=CC=CC=2)=O)=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C(OCC)C>[NH2:29][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NOP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1ccc[nH]1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1N
Temperature: -5 °C
Yield: 82.5 %

Procedure:
Sodium hydride (4.40 g, 0.11 mol, 60% in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at −5° C., methyl 1H-pyrrole-2-carboxylate (11.0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277 ml more of DMF was added and then 0-(diphenylphosphoryl)hydroxylamine (32.8 g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4 h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (×5H2O) was added and the mixture was warmed to 80° C. for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81.1% yield) of the final compound were obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=O)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2].[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([NH:65][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1, 14-dihydroxy-12-[2'-(3"-methoxy-4"-oxocyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ] octacos-18-ene-2,3,10,16-tetraone from Example 24 (79.7 mg) in dry isopropyl alcohol (3 ml) is added benzylamine (86.5 mg). The mixture is stirred at r.t. for 30 min., and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[Cl:29]C1C=C2C(=CC=1)NC(=O)C2>>[Cl:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: O=C1Nc2ccc(Cl)cc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (Example A57), except substituting 5-chlorooxindole (14 mg, 0.08 mmol), the title compound was prepared as an orange solid (13.5 mg, 42%). 1H NMR (400 MHz, d6-DMSO) δ 13.63 (br s, 1H), 10.78 (br. s, 1H), 8.56 (d, J=4.0 Hz, 2H), 8.40 (d, J=10.0 Hz, 1H), 7.91 (s, 1H), 7.89 (d, J=13.2 Hz, 2H), 7.72 (d, J=3.5 Hz, 2H), 7.57 (d, J=12.0 Hz, 1H), 7.52 (d, J=12.0 Hz, 2H), 7.30 (d, J=10.0 Hz, 1H), 6.90 (d, J=11.5 Hz, 1H); MS ESI 399.2 [M+H]+, calcd for [C23H15ClN4O+H]+ 399.09.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:6]=1[CH2:7]Cl>O.[Cl-].C1([N+](CC)(CC)CC)C=CC=CC=1>[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:6]=1[CH2:7][C:1]#[N:2]
Reactant: Fc1ccc(F)c(CCl)c1F
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1c(F)ccc(F)c1F
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
To a solution of sodium cyanide (1.94 g) in water (4 ml) is added phenyltriethylammonium chloride (0.09 g), and thereto is added with stirring 2,3,6-trifluorobenzyl chloride (5.0 g), and the mixture is stirred at 90° to 100° C. for 40 minutes. The reaction mixture is poured into water (20 ml) and is extracted with diethyl ether. The extract is dried over potassium carbonate and the solvent is distilled off to give 2-(2,3,6-trifluorophenyl)acetonitrile (3.1 g), b.p. 80°-85° C. (5 mmHg).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[OH:34][C:28]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:21])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:32][CH2:33]1
Reactant: Oc1ccccc1C1(O)CCNCC1
Reactant: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN1CCC(O)(c2ccccc2O)CC1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 29.1 %

Procedure:
In 50 mL of anhydrous dimethylformamide were dissolved 2.24 g (6.7 mmol) of methyl 4-bromo-2,2-diphenylbutyrate and 1.30 g (6.7 mmol) of 4-(2-hydroxyphenyl)-4-piperidinol. To the resulting solution was added 1.07 g (10 mmol) of sodium carbonate, followed by stirring under heating at 50° C. for 35 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethyl acetate, followed by washing with water and drying. The residue obtained by concentrating the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 870 mg (yield: 29.2%) of methyl 4-(4-hydroxy-4-(2-hydroxyphenyl)piperidino)-2,2-diphenylbutyrate was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][OH:17])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NC(CO)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc2sc(NC(CO)c3ccccc3)nc2c1

Procedure:
A mixture of 116 parts of N-(2-chloro-5-nitrophenyl)-N'-(2-hydroxy-1-phenylethyl)thiourea, 50 parts of potassium carbonate and 675 parts of N,N-dimethylacetamide is stirred and refluxed for 1 hour. The reaction mixture is poured onto 2000 parts of water. After cooling, the whole is filtered over Hyflo and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 23 parts of β-(5-nitro-2-benzothiazolylamino)benzeneethanol.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[NH2:11])[CH:7]=[CH:8][CH:9]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[S:27]>C(Cl)Cl>[C:6]1([CH2:10][C:10]([NH:11][C:26]([NH:25][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[S:27])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:23])([F:24])[F:1])[CH:5]=2)[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: NC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(C(Cc2ccccc2)(NC(=S)Nc2cccc(C(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of bis(3-(trifluoromethoxy)phenyl)methanamine (20 mg, 0.057 mmol) in CH2Cl2 (0.1 mL) was added 1-isothiocyanato-3-(trifluoromethyl)benzene (35 mg, 0.17 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford 1-(2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-(trifluoromethyl)phenyl)thiourea (Example 284) as white lyophillate (30 mg, 81%). LCMS: RT=4.51 min [M+H] 645.14 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[O:11]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cccc2c1O[C@@H](CO)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol (5.00 g, 25.7 mmol) in dichloromethane (250 mL) is added p-toluenesulfonyl chloride (9.82 g, 51.5 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.15 mmol), and N,N-diisopropylethylamine (8.32 g, 64.4 mmol) and the reaction mixture is heated to 50° C. for 12 h. The reaction mixture is quenched by the addition of water (500 mL). The aqueous layer is separated and extracted with dichloromethane (200 mL). The combined organic extracts are washed with aqueous hydrogen chloride (1.0 M, 200 mL), water (200 mL), aqueous sodium chloride (200 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) provides 6.45 g (72%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a white crystalline solid. [α]D25=−20.30 (c 13.1 in chloroform, 40% ee); Rf=0.71 (silica, ethyl acetate:hexanes 2:3); mp 115-117° C.; Anal. Calcd. for C18H20O5S: C, 62.05; H, 5.79. Found: C, 61.99; H, 5.81.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[C:12]2[CH3:24])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[C:12]2[CH3:24])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccccc2)n1S(=O)(=O)c1cccc(Cl)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1cccc(Cl)c1
Yield: 70.1 %

Procedure:
Using {1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}methanol (340 mg), tetra-n-propylammonium perruthenate (17.7 mg), N-methylmorpholine N-oxide (179 mg) and molecular sieves 4A powder (189 mg), a procedure as in Reference Example 6 was performed to give the title compound as a brown oil (yield 237 mg, 70%).
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.C1COCC1>CO.CCOCC.[Pd]>[CH3:1][CH:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2
Reactant: C=C1C(=O)C2CCN1CC2
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC1C(=O)C2CCN1CC2
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
2-Methylenequinuclidin-3-one (17.8 g, 0.13 mol, 1 eq) is dissolved in 40 mL MeOH in a Parr hydrogenation bottle. A THF slurry of 10% Pd/C (0.57 g) is added. The mixture is hydrogenated for 45 min at 45 psi, recharging as needed. The mixture is filtered through a pad of Celite. The Celite is washed with excess MeOH. The solution is concentrated to give a solid and a yellow oil. The mixture is taken up in ether, filtered and concentrated to provide 16.2 g (90%) of 2-methylquinuclidin-3-one. MS (ESI) for C8H13NO m/z 140.2 (M+).
Reaction SMILES: [Br:1][C:2]1(OC)[C:9]([OH:10])=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O.CN([CH:30]=[O:31])C>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:31][CH3:30])[C:9]=1[O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:5]=[O:6]
Reactant: CN(C)C=O
Reactant: COC1(Br)CC(C=O)=CC=C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Product: COc1cc(C=O)cc(Br)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromovanillin (1.16 g, TCI) in anhydrous DMF (20 ml) was added with imidazole (408 mg, TCI), added dropwise with a solution of 4-(N,N-dimethylamino)pyridine (25 mg) and t-butyldimethylsilyl chloride (904 mg, TCI) in DMF (15 ml) under ice cooling, stirred 30 minutes, then warmed to room temperature, and further stirred 3 hours. The reaction mixture was added with water (100 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (Intermediate 16, 1.75 g).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)nc1-2

Procedure:
The title compound was prepared firom 7-methoxy-4,5-dihydronaphto[1,2-D][1,3]thiazol-2-amine hydrobromide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.3 mg) with purity >90%. MS (pos) m/z 455.1, 457.1.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2[C:14]3=[C:15](O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@](O)(C(C)=O)C2)C[C@H](N)[C@@H]1O.Cl.[CH2:40]([OH:47])[C:41]([NH2:46])([CH2:44][OH:45])[CH2:42]O.[CH2:48]([OH:55])[C:49]([NH2:54])([CH2:52]O)[CH2:50][OH:51].Cl>CO.O=O>[CH3:52][C:49]1([CH2:48][OH:55])[NH:54][C:14]([C:13]2([CH3:12])[NH:46][C:41]([CH2:40][OH:47])([CH3:42])[CH2:44][O:45][C:18]2=[O:19])([CH3:15])[C:9](=[O:8])[O:51][CH2:50]1
Reactant: NC(CO)(CO)CO
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Agent: O=O
Solvent: CO
Product: CC1(CO)COC(=O)C(C)(C2(C)NC(C)(CO)COC2=O)N1
Reaction time: 0.33 h

Procedure:
A test similar to that described for the same reaction in methanol solvent (vide supra) was run. Oxomorpholinyl dimer DHM3 (1.38 mg, 4.37×10-3 mmol) was dissolved in 0.5 ml of oxygen-free methanol and quickly transferred without delay into one compartment of the cell. The solvent was promptly removed under vacuum. Daunorubicin hydrochloride (11.9 mg) was dissolved in 100 ml of an aqueous solution of Tris (24.2 mg) and Tris hydrochloride (31.6 mg) and 2.6 ml of this solution (4.18×10-4 mmol of 6) was introduced into the other compartment of the cell. The sample was freeze-thaw degassed over three cycles as described above, sealed, and placed in a thermostatted cell holder at 10.0±0.1° C. for about 20 min prior to mixing. Full spectra between 320 and 800 nm were recorded every 10 sec for the first 125 sec, and then every 20 sec. From the absorbance change at 620 nm over the first 85 sec (50% reaction of daunorubicin), a non-linear least-squares treatment gave a first order rate constant for bond homolysis of DHM3 (k1) equal to 6×10-4 sec-1 and a first order rate constant for destruction of 7 (k2) equal to 2×10-2 sec-1. Treatment of the data obtained in the 164-225 sec interval gave k2 =2.8×10-2 sec-1.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:17]=O)[C:8]3[C:13]([C:14]=2[Cl:16])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22]>>[ClH:1].[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH2:17][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[C:8]3[C:13]([C:14]=2[Cl:16])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c2ccccc2c(Cl)c2c(Cl)cccc12
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NCc1c2ccccc2c(Cl)c2c(Cl)cccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 4,10-dichloro-9-anthracenecarbaldehyde (5B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((4,10-dichloro-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 261°-262° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH:29]([N:24]1[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]1)([CH3:31])[CH3:30]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C(C)C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C(C)C)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=446.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([O:23]CC)=[O:22])=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([OH:23])=[O:22])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-c2cscn2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1Nc1ccc(-c2cscn2)c(F)c1
Yield: 91.7 %

Procedure:
To a suspension of ethyl 2-chloro-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxylate (186 mg, 0.491 mmol) in THF (4 mL), aq. 1N LiOH (1.00 mL, 1.00 mmol) was added. The suspension became clear with stirring. The mixture was then stirred at room temperature overnight. Upon acidification of the mixture with 1N HCl, white solids precipitated out, which were collected, and dried on vacuum to give 2-chloro-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxylic acid (158 mg). MS 351.2 and 353.3 (M+H, Cl pattern)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18].C(O[C:22](=[NH:24])[CH3:23])C.[C:25]([OH:28])(=[O:27])[CH3:26]>C(#N)C>[C:25]([OH:28])(=[O:27])[CH3:26].[NH:24]=[CH:22][CH2:23][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18]
Reactant: CCOc1cc(Cl)c(-c2c(C)n[nH]c2N)c(Cl)c1
Reactant: CCOC(C)=N
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOc1cc(Cl)c(-c2c(C)n[nH]c2NCC=N)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazole (4.8 g) in acetonitrile (50 mL) add ethylacetimidate (free base, 2.3 mL) followed by acetic acid (0.96 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 5.02 g of (iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol-5-yl]amine acetate salt as a white powder.