Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[S:13][C:14]([C:18](O)=[O:19])=[C:15]([CH3:17])[N:16]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:14]2[S:13][C:12]([CH3:11])=[N:16][C:15]=2[CH3:17])=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CCO)c1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cccc(CCO)c2)s1
Reaction time: 14 h
Yield: 73 %

Procedure:
2-(3-Aminophenyl)ethanol (1.202 g, 8.76 mmol) was added to a solution of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (1.652 g, 10.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.015 g, 10.51 mmol) and 1-hydroxybenzotriazole (1.420 g, 10.51 mmol) in dry DMF (20 mL). The mixture was stirred for 14 h then the DMF was removed under reduced pressure and the residue was partitioned between DCM and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel, eluting with ethyl acetate-cyclohexane (1:1 to 1:0) affording the title compound in 73% yield (1.772 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 90 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (2.01 g) in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine (2.24 g). The resulting solution was stirred at room temperature for over night. The solvent was removed by reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (0.776 g). m/z 278. A mixture of morpholine (0.256 mL), 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (776 mg) and DIPEA (0.742 ml) in n-butanol (14.0 ml) was heated at 90° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (310 mg). 1H NMR 9.80 (s, 1H) 5.66 (s, 1H) 3.77 (s, 3H) 3.64-3.71 (m, 4H) 3.53-3.64 (m, 4H); m/z 329.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:37])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:38][C:39]1(C)[O:44]C(=O)C[C:41](=O)[O:40]1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.COC(C)(C)C>[CH3:41][O:40][C:39](=[O:44])[CH2:38][C:25](=[O:27])[C@H:24]([N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.9011 g, 13.9 mmol) in toluene (3 ml) is added to a stirred mixture of (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid (1, 4.179 g, 12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2, 1.7815 g, 12.36 mmol) and dimethyl-pyridin-4-yl-amine (2.0943 g, 16.8 mmol) in toluene (32 ml) at 29-31° C. over a period of approx. 1 hour. Toluene (1 ml) is used for rinsing. Stirring at 29-31° C. is continued for approx. 3 hours. After cooling to ca. 0° C., a 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C., until pH 2-3 is reached. Stirring is stopped and the layers are allowed to separate. The mixture is slowly stirred and filtrated cold (0-5° C.) and the filter cake is rinsed with toluene (12 ml, 0-5° C.). The layers of the filtrate are allowed to separate at approx. 0-5° C. The lower, aqueous layer is separated. The upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3) is passed through a filter charged with anhydrous sodium sulfate (5 g) at 0-5° C. and the filtrate is added to a reactor, containing methanol (18 ml, 20-25° C.). The filter cake is rinsed with toluene (5 ml) and the filtrate is also added to the reactor. The resulting solution is heated (mantle temperature ca. 68° C.) and stirred at approx. 63° C. for approx. 4 hours, then concentrated at a mantle temperature of approx. 50° C. under reduced pressure to obtain an oily residue, which is dissolved in tert-butyl methyl ether (24 ml) at normal pressure and a mantle temperature of ca. 50° C., then concentrated again under reduced pressure to obtain (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-1-oxo-pentanoic acid methyl ester (4) as an oily residue. The residue is dissolved again in tert butyl methyl ether (24 ml) at normal pressure and a mantle temperature of 50° C., then cooled to 18-22° C. and used as such in the next step.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH:36]=O>C1COCC1>[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1/[CH:36]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.39 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (97 mg, 0.35 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (0.37 mmol, crude) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20% →30% EtOAc/CH2Cl2, gradient) afforded 100 mg (68%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([O:8][C:18](=[O:20])[CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=1)=[O:17]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2cc(F)ccc2c1
Yield: 49.9 %

Procedure:
To a solution of 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (2 g, 8.4 mmol) in acetic anhydride (10 mL) was added sodium acetate (0.83 g, 10.1 mmol). After being heated at reflux for 6 hours, the mixture was concentrated in vacuo. The residue was dissolved in 1 N hydrochloric acid (20 mL). The aqueous solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (10-20% ethyl acetate in petroleum ether) to afford 4-acetoxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (1.1 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 8.00 (dd, J=9.09, 5.56 Hz, 1H), 7.89 (s, 1H), 7.50 (dd, J=9.85, 2.53 Hz, 1H), 7.37 (td, J=8.59, 2.53 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.[C:16]([C-:18]([C:21]#[N:22])[C:19]#[N:20])#[N:17].[K+]>>[NH2:22][C:21]([NH:10][CH2:9][CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:18]([C:19]#[N:20])[C:16]#[N:17]
Reactant: NCCCc1ccccc1
Reactant: N#C[C-](C#N)C#N
Agent: CS(=O)(=O)O
Agent: [K+]
Product: N#CC(C#N)=C(N)NCCCc1ccccc1
Yield: 70.8 %

Procedure:
In a similar manner 27.4 g of benzylethylamine and 13 ml (19.2 g) of methanesulfonic acid were allowed to react. The resulting salt was treated with 25.8 g of potassium tricyanomethanide to yield an additional 32 g of 3-amino-3-(benzylethylamino)-2-cyanopropenenitrile, mp 165°-167°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Solvent: CO
Product: COC(=O)CC1NC(=O)c2ccccc21
Reaction time: 3.5 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., supra, 130 g, 0.682 mol) in methanol (1300 ml) containing 6.5 g of p-toluenesulfonic acid is refluxed with stirring for 3.5 hr. Most of the methanol is evaporated and the residue is dissolved in chloroform. The solution is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue (125 g) is crystallized from isopropanol to give methyl 2,3-dihydro-3-oxo-1H-isoindole-1-acetate, mp 136°-138° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, 18 mg of isoamyl nitrite was added dropwise to a mixture of 0.16 g of methyl 2-[3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate, 63 mg of copper (I) chloride, 129 mg of copper (II) chloride, and 1.5 ml of acetonitrile at 0° C., and the mixture was stirred for 1 hour and further stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of 1N hydrochloric acid and ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of methyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate (compound b-6) as a mixture of diastereoisomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:34][NH:35]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](NC(=O)Cc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)Cc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
To N-{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}-2-phenylacetamide (105 mg, 0.236 mmol) in ethanol (2 mL) into a 5 mL sealable vial was added hydrazine (0.22 mL, 7.1 mmol), and the reaction was then capped and heated on a hot plate at 100° C. overnight. The reaction was concentrated, then redissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (30 ml/min, 15% CH3CN/H2O, 0.1% TFA to 45% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the resulting aqueous mixture was added sat. aqueous NaHCO3, and then it was extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (44 mg) as a light yellow solid. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.8 Hz, 3H), 1.61-1.76 (m, 4H), 2.57-2.68 (m, 1H), 3.44 (s, 2H), 3.59 (dd, J=7.7, 3.4 Hz, 1H), 4.38-4.84 (m, 2H), 5.38 (s, 2H), 6.11 (bs, 2H), 6.56 (s, 1H), 7.21-7.36 (m, 5H), 7.54 (dd, J=8.6, 1.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 11.51 (s, 1H).
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].O1CCCC1>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
Solvent: O
Solvent: C1CCOC1
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:
Ansamitocins (3.0 g, 4.72 mmol) were weighed into a three necked flask equipped with a thermometer. Tetrahydrofuran (15 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 (56 mL, 37.7 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 (7.7 mL) was added dropwise to the −35° C. reaction to give a basic quenched mixture. The basic quenched mixture was analyzed after set holding periods by the thin layer chromatography assay described in Example 6. The compound of Formula (I) was detected after holding for 5 and 15 minutes. After 30 min a sample of 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, 15 mL and 88% formic acid, 1.85 mL) was then added to the flask followed by 66 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 precipitated aluminum byproducts were removed by vacuum filtration. Solvent was evaporated from the filtrate by rotary evaporation under vacuum. Butyl acetate 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 2.2 g of maytansinol (85% yield by weight).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9](Br)=[CH:8][CH:7]=2.C[S-].[Na+].[CH3:28][S:29]C>>[NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([S:29][CH3:28])=[CH:8][CH:7]=2
Reactant: CSC
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: C[S-]
Agent: [Na+]
Product: CSc1ccc2c(=O)n(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (0.19 g, 0.50 mmol), sodium thiomethoxide (0.043 g, 0.60 mmol) and dimethylsulfide (2 mL) was stirred at 70° C. for 2 h. To the reaction mixture was added another sodium thiomethoxide (0.043 g, 0.60 mmol), and the resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The extracts were combined and washed once each with saturated aqueous sodium hydrogencarbonate (25 mL) and saturated brine (25 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5 (v/v)) to give 3-(aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone (0.16 g, 88%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
A solution of methyl 5-chloro-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-4-[(trimethylsilyl)ethynyl]benzoate (9.3 g, 20 mmol) and (3-fluorophenyl)boronic acid (4.3 g, 30 mmol) in toluene (200 mL) was treated with water (200 mL) saturated with sodium bicarbonate (3.4 g, 40 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol), degassed with nitrogen for 10 minutes, and heated at 80° C. for 6 hours. The reaction mixture was cooled to 20° C. and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to a crude residue. The crude material was diluted with dichloromethane and adsorbed onto 36 g of silica gel. Purification by flash column chromatography using ethyl acetate in hexanes (0%-40%) gave the desired product (7.1 g, 86%). LCMS for C19H18ClFNO4Si (M+H)+: m/z=406.1; Found: 405.7.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([Cl:21])=[O:17])[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(C(=O)Cl)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 390 mg, 1.69 mmol), was dissolved in dichloromethane (26 mL) and cooled to 0° C. Oxalyl chloride was added (0.79 mL, 8.47 mmol) along with 1 drop of DMF. The ice bath was removed and the mixture was stirred at rt for 30 min before the solvent was evaporated. The residue was used in the next step with no further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:27][N:26]=[N:25][N:18]=2)=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)cn1
Temperature: 120 °C
Reaction time: 7 h
Yield: 30.1 %

Procedure:
2-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-5-cyanopyridine (reference example 10) (0.45 g, 1.16 mmol) in N-methylpyrrolidone (12 ml) was treated with sodium azide (228 mg, 3.5 mmol) followed by triethylammonium chloride (251 mg, 1.8 mmol) and heated with stirring at 120° C. (oil bath) for 7 hours under an argon balloon. The resultant red solution was poured into ice/water (30 ml), acidified and extracted twice with ethyl acetate (total 50 ml). The combined organic extracts were washed twice with water, dried (MgSO4) and evaporated to give a brown gum. The gum was purified by MPLC to give the title compound as an off-white foam (150 mg, 30%).