Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[S:38]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[S:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=S)o4)cc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in THF (0.6 mL) at −78° C was added thiophosgene (0.010 mL). After stirring for 1 h at −78° C, the reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography, eluting with mixtures of EtOAc in hexanes, to provide the title compound. LC/MS: m/e 562.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.22 (1H, d, J=1.8 Hz), 7.82 (1H, dd, J=8.4, 2.0 Hz), 7.65 (1H, d, J=7.4 Hz), 7.17 (1H, d, J=7.5 Hz), 7.13-7.16 (2H, m), 7.10 (1H, br s), 6.97-6.99 (2H, m), 6.88 (1H, d, J=8.5 Hz), 4.70-4.95 (2H, br), 1.25 (9H, s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CCONC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: C1CCN(C2CCC3(CC2)OCCO3)OC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (358.5 mg, 2.3 mmol), and 1,2-oxazinane (200 mg, 2.3 mmol), and sodium triacetoxyborohydride (1.46 g, 6.9 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated. Residue purified by silica column chromatography to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]([NH:22][C:23](OCC)=O)[CH2:14][CH2:13]1)=O)C>C1COCC1>[CH3:10][N:12]1[C:16]2([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:15]([NH:22][CH3:23])[CH2:14][CH2:13]1
Reactant: CCOC(=O)NC1CCN(C(=O)OCC)C12CCCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCN(C)C12CCCCC2
Reaction time: 48 h
Yield: 55.4 %

Procedure:
To a stirring solution of 2.4 g of lithium aluminum hydride (LAH) in 200 ml of THF was added in a dropwise manner 6.5 g of 1-ethoxycarbonyl-4-(ethoxycarbonylamino)-1-azaspiro[4.5]decane of Example 10 in 70 ml of THF. The resultant mixture was refluxed overnight, and then kept at room temperature for 48 hours. The excess LAH was destroyed with water, and the resultant mixture was filtered, washed with ether and then evaporated and then distilled at 55° C., 0.1 mm to yield 2.2 g of 1-methyl-4-methylamino-1-azaspiro[4.5]decane.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[OH-].[Na+].O.CC(C)(O)C#N>[CH2:20]([N:22]1[C:26]([OH:27])=[C:25]([C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:14]([Cl:15])[C:6]=2[Cl:5])[CH:24]=[N:23]1)[CH3:21]
Reactant: CCn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Agent: CC(C)(O)C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (3.5 g, 6.7 mmol) was added to a slurry of 1.3 g (4.8 mmol) of 2,3-dichloro-4-methylsulfonylbenzoic acid in 10 mL of toluene with stirring and the mixture was heated at reflux until a homogeneous solution was obtained, which required about 45 min. The volatile components of the mixture were removed by evaporation under reduced pressure and the residual acid chloride was taken up in 10 mL of dichloromethane. This solution was combined with a solution of 5.4 g (4.8 mmol) of 1-ethyl-5-hydroxypyrazole dissolved in 6.2 mL of 1 N aqueous sodium hydroxide solution diluted with 5 mL of water with stirring at ambient temperature. After 1 hour, the pH was adjusted to 8 by adding 1 M aqueous sodium bicarbonate. The phases present were separated and the aqueous phase was extracted with 3 mL of dichloromethane. The organic phase and extract were combined, washed with 5 mL of water, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was taken up in 15 mL of anhydrous dioxane and 730 mg (5.3 mmol) of solid potassium carbonate was added. The mixture was heated at 90° C. with stirring for 2 hours and then another 100 mg of potassium carbonate and 2-3 drops of acetone cyanohydrin were added. Heating and stirring were continued for another 30 min and then the mixture was cooled and poured into 15 mL of water. The phases were separated and the aqueous phase was extracted with 2×5 mL of dichloromethane. The aqueous phase was then acidified with 6 N aqueous hydrochloric acid and the solids that formed were extracted with 2×5 mL of dichloromethane. All of the organic phases and extracts were combined, washed with 5 mL of water, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue, which amounted to 1.4 g (80 percent of theory), was recrystallized from aqueous ethanol to obtain the title compound as a white solid melting at 198-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-])=O.N1CCOCC1>C(O)C.CO.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[NH2:17]
Reactant: Cc1ccc(/C=C\c2ccccc2Br)c([N+](=O)[O-])c1
Agent: [Rh]
Solvent: CCO
Solvent: CO
Solvent: C1COCCN1
Product: Cc1ccc(CCc2ccccc2Br)c(N)c1
Yield: 92.7 %

Procedure:
A solution of the above nitrobenzene (9.68 g, 30.3 mmol) in ethanol (110 ml) and methanol (40 ml) was hydrogenated 2 h at 3 MPa in the presence of morpholine (0.6 ml) and Rh/C (KO 319) catalyst (2 g). The catalyst was filtered off, the filtrate evaporated in vacuo and the residue was stripped with toluene (3×20 ml). The oily residue crystallized after standing at room temperature. After washing the solid with petroleum ether and drying, 2-(2-(2-bromophenyl)ethyl)-5-methylaniline (8.15 g, 92%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(-c2ccc(-c3ccc(-c4ccccn4)nn3)nn2)nc1
Yield: 62 %

Procedure:
Stille coupling starting from the 6,6′-dichloro-3,3′-bipyridazine 17 was subsequently carried out in the presence of two mol of tributylstannylpyridine 18 and 10% of Pd(PPh3)4 catalyst, so as to give a new 6,6′-bis(pyridin-2-yl)-3,3′-bipyridazine 19 with a yield of 62% (Scheme 8). In parallel, the formation of the homocoupling product 21 (23%) was observed. The use of an excess of organostannane makes the purification of the dimer more difficult.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Br:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O>[Br:10][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(O)Cc1cccs1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 m mol) in HOAc (10 ml) was added dropwise bromine (2.25 g, 14 mmol) at 10-20° C. for 30 min. The mixture was allowed to warm to room temperature for 3 hours. Then it was diluted with water (100 ml), neutralized to pH=5 with anhydrous sodium carbonate and extracted with EtOAc (100 ml×3). Dried over Na2SO4, filtered and concentrated to afford crude product as brown oil. MS (ESI): m/z 220.9 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]#[C:20][CH2:21]Cl)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[Na+].[I-].[CH3:26][NH:27][CH2:28][CH2:29][CH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]#[C:20][CH2:21][N:27]([CH3:26])[CH2:28][CH2:29][CH3:30])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCCNC
Reactant: CN(C[C@H]1CC[C@H](C#CCCl)CC1)C(=O)Oc1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)CC#C[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 250 mg (0.63 mmol) of trans-[4-(3-chloro-prop-1-ynyl)cyclohexyl-methyl]-methyl-carbamic acid 4-fluoro-phenyl ester with a catalytic amount of NaI in 7 ml of methanol was treated with 0.65 ml (6.3 mmol) of N-methylpropylamine and stirred over night at room temperature. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/ether (3×). The organic phase was dried with sodium sulfate, filtered and evaporated. Purification by flash column chromatography on silica gel (methylenechloride/methanol 98:2) gave 218 mg (93%) of pure trans-methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexylmethyl}-carbamic acid 4-fluoro-phenyl ester as light brown oil, MS: 375 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+].C(OCC)C>C(O)C>[C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Temperature: 40 °C
Yield: 56.4 %

Procedure:
5.33 g (15.6 mmol) of tert-butyl 4-(5-ethoxycarbonylthiazol-2-yl)piperazine-1-carboxylate [Precursor BBB60] were dissolved in ethanol together with 0.96 g (17.1 mmol) of KOH (100 ml) and stirred at 40° C. 4 h. The resulting precipitate was filtered off and dissolved in water. After this, the solution was adjusted to a pH<2 with 10% strength hydrochloric acid and extracted with chloroform. The organic phase was washed with water and a satd aq. NaCl soln and dried over MgSO4. After filtration and concentration in vacuo, 2.77 g (8.8 mmol, 56%) of tert-butyl 4-(5-carboxythiazol-2-yl)piperazine-1-carboxylate were obtained from the residue by recrystallization from diethyl ether.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20].[C:21]([O:25][C:26]([N:28]([CH3:34])[C@@H:29]([CH3:33])[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:34][N:28]([C@@H:29]([CH3:33])[C:30](=[O:31])[NH:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20])[C:26](=[O:27])[O:25][C:21]([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 84.5 %

Procedure:
To a mixture of (S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (500 mg, 1.71 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (348 mg, 1.71 mmol, Eq: 1.00), O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU, 682 mg, 1.8 mmol, Eq: 1.05) and 1-hydroxybenzotriazole hydrate (HOBT120, 243 mg, 1.8 mmol, Eq: 1.05) in DMF (5 mL) was added N,N-diisopropylethylamine (DIEA, 553 mg, 4.28 mmol, Eq: 2.50). The mixture was stirred for 45 min., diluted with 50 mL EtOAc and washed H2O, 2% KHSO4, 5% NaHCO3 and 5% brine. The organic solution was dried over Na2SO4, filtered and concentrated to give the title compound (525 mg, 84%) as a tan foam which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:22]Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[Br:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.00 g, 9.51 mmol) and K2CO3 (3.94 g, 28.5 mmol) in DCM (120 mL), in the dark, was added Br2 (1.46 mL, 28.5 mmol) slowly under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was quenched with saturated aqueous Na2S2O3 (50 mL). The organic layer was separated and washed with H2O (50 mL) and brine (50 mL), then dried with Na2SO4. Removal of the solvent under reduced pressure yielded a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.40 (q, J=7.1 Hz, 2H), 4.08 (s, 3H), 1.43 (t, J=7.1 Hz, 3H), 1.42 (m, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C11H17BrN2O2: 289.1 (M+H), Measured: 289.1.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1.C(Cl)(Cl)Cl.CC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
A solution of 300 mg (0.35 mmole) of taxol, 500 mg (4.2 mmole) of succinic anhydride and 10 mg of DMAP in 4 mL of DMF is heated at 85° C. for 10 h (single spot by TLC using silica, chloroform/acetone, 9:1). With the use of the same procedure as for 2'-succinyltaxol above, the crude product is isolated, and chromatographed on 5 g of silica using toluene/10-50% acetone. This gave 300 mg (68%) of crystalline material: mp 180°-1° C.; [a] -30.1° (c=1.05, EtOH); Anal. (C H NO) C,H,N.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1>ClCCl>[CH3:1][N:2]([CH3:3])[C:5]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1cccc2c(Cl)ncnc12
Reactant: CNC
Solvent: ClCCl
Product: CN(C)c1ncnc2c(O)cccc12

Procedure:
Dimethylamine gas is bubbled slowly through a solution of 4-chloro-8-quinazolinol (0.7 g, 3.88 mmol) in dichloromethane, under a nitrogen atmosphere, at 3° C. for 20 minutes. The cooling bath is removed and dimethylamine gas is bubbled through the reaction mixture for an additional 30 minutes. The reaction mixture is then concentrated in vacuo to obtain a grey solid. The solid is washed with water and extracted with 10% sodium hydroxide solution. The combined extracts are acidified to pH 7.0 and extracted with dichloromethane. The organic extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product as a grey solid, 0.36 g, mp 104°-105° C.
Reaction SMILES: BrC1C=[CH:6][C:5]([O:8]C(C)C)=[C:4](C(C2C=CC(C)=CC=2)=C)C=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[CH2:30])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:8][CH:5]([CH3:6])[CH3:4])([OH:28])[CH:24]([C:29]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[CH2:30])[CH:23]=1
Reactant: C=C(c1cccc(C)c1)c1cc(Br)ccc1O
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Product: C=C(c1cccc(C)c1)C1C=C(Br)C=CC1(O)OC(C)C

Procedure:
Employing the same general procedure as for the preparation of 4-bromo-1-isopropoxy-2-[(1-p-tolyl)vinyl]benzene (Compound S), 81.5 mg (0.3 mmol) of 4-bromo-2-[(1-m-tolyl)vinyl]phenol (Compound N) was converted into the title compound using 164 mg (0.6 mmol) of triphenylphosphine, 0.10 mL (108 mg, 0.6 mmol) of diethylazodicarboxylate, 0.05 mL (39 mg, 0.6 mmol) of isopropanol and 3 mL of tetrahydrofuran. The reaction was sluggish necessitating addition (after 23 hours of stirring at ambient temperature) of another equivalent of reagents (initially only ½ of the above amounts were added) and stirring for 4 additional days. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a pink oil.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]
Reactant: O=C1Nc2ccccc2C12COc1cc3nccnc3cc12
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3nccnc3cc12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7H-spiro[furo[2,3-g]quinoxaline-8,3′-indolin]-2′-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (93%) as a pale orange solid: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ8.64 (m, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77-7.67 (m, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 5.56 (d, J=16.5 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.91 (d, J=16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.5, 155.9, 149.4, 144.9, 142.3, 142.1, 139.8, 139.8, 136.9, 132.6, 132.4, 128.8, 123.3, 123.2, 122.6, 121.9, 121.4, 116.6, 109.6, 82.6, 57.7, 46.5; MS (ES+) m/z 381.2 (M+1).
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])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21]O)[N:20]=[C:15]2[CH:14]=1.C(Cl)Cl.S(Cl)(Cl)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>O>[N:39]([CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3nc(CN=[N+]=[N-])cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A flask was charged with (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (4.00 g, 9.12 mmol, Preparation #F.1), DCM (90 mL) and thionyl chloride (0.732 mL, 10.0 mmol). The mixture was stirred at rt for about 40 min and concentrated under reduced pressure. The residue was dissolved in DMF (90 mL) and treated with NaN3 (1.48 g, 22.8 mmol). The mixture was stirred overnight at rt. The solution was diluted with water (150 mL). The suspension was extracted with EtOAc (3×125 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (4.23 g, 100%): LC/MS (Table 2, Method b) Rt=3.16 min; MS m/z 464 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH:11]1([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)[N:17]=2)[CH2:13][CH2:12]1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.[BH3-]C#N.[Na+]>>[CH:11]1([NH:14][C:15]([C:16]2[N:17]=[C:18]([C:22]3[CH2:23][CH2:24][N:25]([CH2:36][C:35]4[CH:38]=[CH:39][C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:33][CH:34]=4)[CH2:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cccc(C2=CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)n1
Reaction time: 12 h
Yield: 23 %

Procedure:
1′-(4-Trifluoromethoxybenzyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (9) was prepared by adding diisopropyl ethyl amine to a suspension of compound 5 (72 mg, 0.25 mmol), 4-trifluoromethoxybenzaldehyde (8) (Aldrich) and 3 Å molecular sieves (200 mg, Aldrich). The mixture was stirred for 12 hours and NaCNBH3 was added. The crude product was filtered and then purified on Prep TLC (10% MeOH in dichloromethane with 1% NH4OH) to provide the title compound 9 (25 mg, yield 23%): 1H NMR (400 MHz, CD3OD, HCl-salt): δ 8.48 (bd, 1 h, NH), 7.88 (d, 1H, J=7.6 Hz), 7.83 (t, 1H, J=7.6 Hz), 7.65 (d, 1H, J=7.6 Hz), 7.57 (m, 2H), 7.32 (d, 2H, J=8.8 Hz), 6.68 (m, 1H), 4.39 (m, 2H), 3.85 (m, 2H), 3.68 (m, 1H), 3.26 (m, 1H), 3.12 (m, 1H), 2.82 (m, 1H), 2.71 (m, 1H), 0.72 m, 2H), 0.54 (m, 2H); MS: 418.