Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:19]([CH3:31])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([OH:33])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:11]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:33][C:6]=2[CH:5]=1)=[O:34]
Reactant: CCC(CC)(C(=O)Nc1ccc(C(=O)OC)cc1O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Temperature: 160 °C
Yield: 72.6 %

Procedure:
A solution of 4-[2-(4-benzyloxy-3-methyl-phenyl)-2-ethyl-butyrylamino]-3-hydroxy-benzoic acid methyl ester (2.15 g, 4.66 mmol) in toluene (50 mL) is treated with TsOH—H2O (443 mg, 2.33 mmol). The reaction is heated to 160° C. for 60 m. The reaction mixture is cooled down, and toluene is removed under vacuum. The residue is purified by column chromatography (10% EtOAc/Hex) to give the title compound as an oil (1.50 g, 72%) MS (ES) m/e: 444.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)CN(C)c1ccccc1
Yield: 76.3 %

Procedure:
The mixture of N-phenylglycine methyl ester (0.99 g, 6 mmol), potassium carbonate (1.66 g, 12 mmol), and iodomethane (1.28 g, 9 mmol) in acetonitrile (20 mL) was refluxed overnight. The solids were filtered and the filtrate was diluted with water (100 mL), extracted with dichloromethane (4×50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to afford the title compound (0.82 g, 77%). 1H NMR (400 MHz, CDCl3) δ: 7.24 (m, 2H), 6.75 (m, 1H), 6.67 (m, 2H), 4.07 (s, 2H), 3.71 (s, 3H), 3.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][O:11]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][P:22]([O-])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][O:11][P:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCC(=O)OCc1ccccc1)OC(C)(C)C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of methanesulfonyloxy-acetic acid benzyl ester (2.50 g, 10.24 mmol) in THF (20 mL) was added the tetrabutylammonium salt of di-tert-butylphosphate (4.61 g, 10.24 mmol). The reaction was stirred overnight, concentrated, and purified directly by MPLC (SiO2, 10-30% gradient elution, Hexane: EtOAc) to give 1.42 g (39%) of (di-tert-butoxy-phosphoryloxy)-acetic acid benzyl ester. 1H NMR (400 MHz, CDCl3): δ 7.37-7.35 (m, 5H), 5.21 (s, 2H), 4.55 (d, 2H), and 1.48 (s, 18H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH3:13][N:14]([CH3:32])[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Br)C=C.Cl>O1CCCC1>[CH3:32][N:14]([CH3:13])[C:15](=[O:31])[CH:16]([CH2:3][CH:2]=[CH2:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)C
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(CCCCCCCCCCCCCC)C(=O)N(C)C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of n-butyl lithium (hexane, 44 mmol) in 120 mL of anhydrous tetrahydrofuran at 0° C., under nitrogen atmosphere it was added 6.2 mL (44 mmol) of diisopropylamine. After 5 min., 10 g (35 mmol) of N,N-dimethylhexadecanamide was added dropwise and the solution was stirred for 1 h at the same temperature. To the solution 3.7 mL (44 mmol) of allyl bromide were added and the mixture was stirred at room temperature for 12 h. Afterwards the solution was poured on water and the resulting mixture was acidified with 12 N HCl, and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and after evaporation of the solvent it was obtained 10.94 g of an oil that was purified by column chromatography (silica gel, hexane: ethyl acetate 15%). In that way, 10.2 g of a colorless oil was obtained (85% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:28]=[N:29][NH:30][N:31]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[Li][Li].[C:37]1([C:43](Cl)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CC(C)=O>[CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31]=[N:30][N:29]([C:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[N:28]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li][Li]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12

Procedure:
A mixture containing the title compound of Example 6, 2-cyclopropy-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid, dilithium salt (906 mg, 2.02 mmol), triphenylmethyl chloride (590 mg, 2.11 mmol), and triethylamine (0.309 mL, 224 mg, 2.22 mmol) in acetone (10 mL) was stirred at room temperature in a stoppered flask for four days (reaction time beyond two days was unnecessary). The reaction mixture was next filtered and re-dissolved into 40 mL total volume with acetone. Yield was assumed to be 100% and appropriate aliquots were used in subsequent reactions.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(NC(C)C)(C)C.Cl.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=2[CH2:23][CH2:22]1.[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([O-])=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[Na+]>CN(C)C=O>[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([N:21]3[C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=4[CH2:23][CH2:22]3)=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: N#Cc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.3 %

Procedure:
242 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 371 mg of N,N-diisopropylamine and 210 mg of 2,3-dihydro-1H-indole-4-carbonitrile hydrochloride are added to a solution of 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, obtained according to example 1c, step 2c, in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up with 100 ml of water and 20 ml of ethyl acetate, and then stirred at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and petroleum ether. The solid obtained is dried with suction, and then dried under reduced pressure at 40° C. 190 mg of 1-{[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}-2,3-dihydro-1H-indole-4-carbonitrile are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.O>CN(C)C=O>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:13])(=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CN1C(C(=O)Cl)=C(O)c2ccccc2S1(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.2 %

Procedure:
1.23 g (4.5 mmols) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide were dissolved in 10 ml of dimethylformamide, and 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine were added in portions thereto. The reaction mixture was stirred for 24 hours at room temperature and was then mixed with 40 ml of water. The aqueous mixture was stirred for 20 minutes at room temperature, and then the precipitate which had formed was filtered off, washed and dried. Recrystallization from dioxane yielded 0.4 g (24% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.CO.CN(C=O)C.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>[Cu]I.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:20]=[N:56][NH:55][N:54]=3)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1
Reactant: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]n4)ccc32)c1NC1CCN(S(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
239 mg of 5-(2,6-difluorophenyl)-3-([1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline, prepared in step 4 of example 7, are introduced into 4 ml of methanol and 4 ml of DMF, and 208 μL of trimethylsilyl azide and 15 mg of copper(I) iodide are added. After 2 h of heating at 100° C., 104 μl of trimethylsilyl azide and 7 mg of copper(I) iodide are added and heating at 100° C. is continued for 2 h. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 121 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow foam). 1H NMR: −0.04 (s, 9 H) 0.90 (m, 2 H) 1.61 (m, 2 H) 2.12 (m, 2 H) 275 (m, 2 H) 2.85 (s, 3 H) 3.57 (m, 2 H) 3.68 (m, 2 H) 4.47 (m, 1 H) 5.66 (s, 2 H) 6.49 (d, J=8.4 Hz, 1 H) 7.36 (t, J=8.0 Hz, 2 H) 7.67 (m, 1 H) 8.01 (broad s, 1 H) 8.25 (broad d, J=8.5 Hz, 1 H) 8.41 (d, J=8.5 Hz, 1 H) 8.43 (partially masked broad m, 1 H) 15.28 (broad m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C@@H:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NCCN(C(=O)C=C)[C@@H](C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[C@H:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][CH2:2][CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CCN)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)N(CCNC(=O)OC(C)(C)C)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
N-(2-Amino-ethyl)-N-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-acrylamide: According to the procedure of Example 1d above, (2-{acryloyl-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester was treated with 50% TFA in CH2Cl2 (3 mL) to give the title compound: MS (ES) m/e 439.2 (M+H)+.
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: C1CCOC1
Solvent: O
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: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].C[O:24][C:25](=O)[CH:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25](=[O:24])[CH:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.0 g, 0.0035 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyoctanoate (0.667 g, 0.0038 mole) was added dropwise to the reaction. The reaction was heated under vacuum for 5 hours. A waxy off-white solid was obtained (crude yield=1.33 g). The waxy solid was recrystalized from hot hexane (yield=0.4 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11](Br)[CH:12]=[CH2:13]>CN(C)C=O>[CH2:13]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:12]=[CH2:11]
Reactant: OCc1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Sodium hydride (4.8 g, 0.2 mol, 50% dispersion in mineral oil) was added under nitrogen at room temperature to benzyl alcohol (21.6 g., 0.2 mol) in 150 ml. of dry dimethylformamide. The suspension was stirred at room temperature for 30 minutes and then heated at 60° C. for 30 minutes. Allyl bromide (24.2 g., 0.2 mol) was added to the suspension dropwise at 50° C. with stirring. The reaction mixture was heated at 90° C. for five and a half hours under nitrogen, cooled and stirred at room temperature overnight. The dimethylformamide was removed on a rotary evaporator and the resulting oil was extracted with ether, dried over sodium sulfate and the ether evaporated off. The resulting oil was purified on a silica gel column using hexane (500 ml) to remove the mineral oil, followed by methylene chloride (750 ml) to elute the desired product. Evaporation of the solvent yielded the title compound as a pale yellow liquid, 16 g., 54% yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C1(C)C=CC=CC=1.CN1C(=O)CCC1>[O:14]=[C:6]1[CH:5]([CH2:4][CH2:3][N:2]2[C:18](=[O:19])[C:17]3[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]2=[O:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: NCCC1C(=O)Nc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C1Nc2ccccc2C1CCN1C(=O)c2ccccc2C1=O
Yield: 56.4 %

Procedure:
A mixture of 3-(2-aminoethyl)indolin-2-one hydrochloride (3.20 g, 15.06 mmol), phthalic anhydride (3.34 g, 22.59 mmol) and TEA (4.56 g, 45.18 mmol) in toluene/NMP (20 mL/10 mL). The mixture was heated under reflux for 3 h. The reaction mixture was concentrated and the resulting mixture was washed with saturated aqueous ammonium chloride and brine. The separated organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (2.60 g, 8.50 mmol, 56% yield) as a brown solid. MS (ESI) m/z 307.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[S:16][CH3:17].[CH3:18][NH2:19].[OH-].[NH4+]>>[CH3:18][NH:19][C:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[S:16][CH3:17])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: CN
Reactant: COc1ccc2c(c1)c(SC)c(C(=O)O)n2C
Agent: [NH4+]
Agent: [OH-]
Product: CNC(=O)c1c(SC)c2cc(OC)ccc2n1C
Yield: 45 %

Procedure:
Prepared from 5-methoxy-1-methyl-3-(methylthio)-1H-indole-2-carboxylic acid by the procedure of Example 1 with 40% aqueous methylamine solution substituted for ammonium hydroxide. Yield 45% after recrystallization from ethyl acetate-hexane; mp 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8]>C(O)C>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:4]([CH2:3][CH2:2][CH2:7][CH2:6][CH3:5])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Solvent: CCO
Product: CCCCCc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Reaction time: 2.5 h
Yield: 160.7 %

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (4.3 mmoles, 0.9 g) and ethyl hexanoamidate hydrochloride were dissolved in 20 ml ethanol and stirred for 2.5 hours. The solvent was removed in wacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried and concentrated. The residue was chromatographed on silica gel eluted with 1:1 ethylacetate/hexane to yield 1.0 g of 5-(2-Cyanophenyl)-2-pentyl-1H-benzimidazole.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]2[CH:21]=[C:20]4[C:27]([CH3:35])([CH3:34])[C:28]5[C:33]([C:19]4=[CH:18][C:17]3=2)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:39]1[N:44]=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:42]=[C:41]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:40]=1>CN(C)C=O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:39]2[N:44]=[C:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:42]=[C:41]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:40]=2)[C:22]2[CH:21]=[C:20]4[C:27]([CH3:35])([CH3:34])[C:28]5[C:33]([C:19]4=[CH:18][C:17]3=2)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2oc2ccccc24)cc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5cccc6c5oc5ccccc56)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.6 g (58.78 mmol) of 7-dibenzofuran-4-yl-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 225 ml of dimethylformamide under a protective-gas atmosphere, and 2.8 g of 60% NaH in mineral oil (70 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (18.6 g, 66.2 mmol) in 75 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 18.3 g (27 mmol, 45.7%).