Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][N+:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]>>[CH3:17][N:18]([CH3:27])[CH:19]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and dimethyl-(2-methyl-benzylidene)-ammonium chloride.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:18])=[C:15]([O:38][CH3:39])[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>CO>[CH2:40]([N:42]([CH2:43][CH3:44])[CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][C:26]4=[O:35])[CH2:23][CH2:24]3)=[O:18])=[C:15]([O:38][CH3:39])[CH:14]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:41]
Reactant: CCNCC
Reactant: C=CS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1-(4-(N-vinylsulfonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (80 mg, 0.14 mmol) from Example 192 in 5 mL of dry MeOH was added diethylamine (0.14 mL, 1.4 mmol) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 98:2 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:21]
Reactant: CCI
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)ccc1OC
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 55.4 %

Procedure:
A mixture of 24.3 g (134 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhyd potassium carbonate and 31.4 g (201 mmol) of ethyl iodide in 500 mL of dimethylformamide was stirred at 100° C. for 5.5 h. An additional amount of ethyl iodide (31.4 g) and potassium carbonate (18.4 g) was added and heating was continued for 2 h more. The reaction was filtered and volatile material was removed from the filtrate in vacuo. The residue was slurried with water and filtered to collect the product which was washed with water and dried. Recrystallization from heptane gave 15.6 g of methyl 3-ethoxy-4-methoxybenzoate as white crystals: mass spectrum (electrospray, m/e): M+H 210.9.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:32]([NH:31][CH2:28][CH2:29][CH3:30])=[O:33])[CH2:16]1)#[N:8]
Reactant: CCCN=C=O
Reactant: N#Cc1c(OCC2CCCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
To a solution of 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 262d) (0.10 g, 0.34 mmol) in THF (6 mL) were added triethylamine (0.10 mL, 0.76 mmol) and propylisocyanate (0.05 mL, 0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogen for 3 hour then filtered and evaporated, to give 3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide (0.13 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 0.81 (t, J=7.2 Hz, 3H), 1.34-1.41 (m, 4H), 1.62-1.64 (bm, 1H), 1.87-1.95 (bm, 2H), 2.64-2.77 (m, 2H), 2.93-2.98 (m, 2H), 3.77 (bd, J=12.8 Hz, 1H), 3.98 (bd, J=12.8 Hz, 1H), 4.09-4.13 (m, 1H), 4.17-4.20 (m, 1H), 6.38 (d, J=5.6 Hz, NH), 7.74 (bdd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.94 (m, 2H). MS 347 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5]2.[N:15]1([CH2:20][CH2:21]O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:11][CH:10]=2)([O-:14])=[O:13]
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1cnc2ccc(O)cc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccc(OCCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
6-Hydroxy-3-nitroquinoline (148 mg, 0.78 mmol) was dissolved in THF (18 mL). 2-(Pyrrolidin-1-yl)ethanol (0.091 mL, 0.78 mmol) and triphenylphosphine (306 mg, 1.17 mmol) were added. Lastly, diethyl azodicarboxylate (0.184 mL, 1.17 mmol) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was then concentrated in vacuo and the residue was purified by flash chromatography (SiO2) to yield 134 mg (60%) of 3-nitro-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline. LC/MS (m/z): 288.1 (MH+), Rt 1.80 minutes.
Reaction SMILES: C([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=O.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:17][O:16][C:14]1[C:15]2[NH:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[C:11]([S:18]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:19])=[O:20])=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Reactant: Nc1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccncc2)c2c1[nH]c1ccccc12
Temperature: 100 °C
Yield: 41 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 5 ml of pyridine. To it was added 4-aminopyridine (0.35 g, 3.7 mM) and the reaction mixture was heated at 100° C. for three hours. The solvent was evaporated and the residue was purified on a silica gel column using MeOH(CHCl3 to obtain the deformylated desired compound as a white solid with a yield of 41% (0.097 g); mp 311-313° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[NH:10][C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)OC(C)(C)C)CC2
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(Cc1cccc(F)c1)C(=O)C(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A suspension of 3-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.0 g, 6.86 mmol), 3-fluorobenzyl bromide (1.68 mL, 13.72 mmol) and Cs2CO3 (4.48 g, 13.72 mmol) in acetonitrile (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness, the residue dissolved in water and extracted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness. Thus obtained crude product was purified by flash chromatography on silica gel column eluted with ethyl acetate/n-hexane (30% of ethyl acetate in n-hexane). The title compound (2.10 g, 77%) was obtained as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cn2)CC1
Yield: 70.3 %

Procedure:
To a stirred solution of 2-bromo-5-methanesulfonyl-pyridine (0.24 g, 1.0 mmol, 1.0 equiv; prepared as described in EP 1298 116 A1 (Pfizer Products Inc., USA)) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol, 1.1 equiv) in acetonitrile (6.0 mL) was added N-ethyl diisopropylamine (0.87 mL, 0.66 g, 5.0 mmol, 5.0 equiv) drop by drop at rt and the reaction mixture heated to reflux for 19 h. The reaction mixture was poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.25 g (70%) of the title compound as light brown oil. MS (ISP): 356.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[CH3:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][Cl:32])=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1nc(C)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1nc(C)ccc1CCl

Procedure:
3.78 g of 6-methyl-2-methoxy-3-pyridinemethanol was dissolved in 60 ml of carbon tetrachloride, 6.48 g of triphenylphosphine was added thereto, and the mixture was heated under reflux for 6 hours 30 minutes. The solvent was evaporated, n-hexane was added to the residue, and the insoluble matters were filtered off. The filtrate was evaporated, and the crude product was purified by silica gel chromatography (n-hexane:ethyl acetate=100:1), to give 2.29 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].Br[CH2:13][C:14]([C:16]1C=CC=C[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([O:11][CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(O)c1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(OCC(=O)CC)c1

Procedure:
A solution of 3-allyloxyphenol (1.19 g), 2-bromoacetophenone (1.0 g) and potassium carbonate (1.10 g) in 2-butanone (15 ml) was refluxed for four hours. The mixture was partioned between 0.2N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo. Column Chromatography (silica gel 60, 50% methylene chloride in hexane) gave the title compound.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[N+:8]1([O-])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd]>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:7])[NH:2][N:1]=1
Reactant: O=c1cccn[nH]1
Reactant: [O-][n+]1ccccc1
Agent: [Pd]
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
Haginiwa et al., [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[N:8]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1)=O.CO>C(N(CC)CC)C>[F:24][C:20]1[CH:19]=[C:18]([S:15]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:7]=[C:6]3[NH2:5])(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12

Procedure:
The crude 2,2,2-Trifluoro-N-[5-(3-fluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-acetamide (46.33 mmol) was treated with methanol (250 mL) and triethylamine (20 mL) and heated to reflux for 36 hours. The volatiles were partially evaporated, cooled and filtered. The solid was washed with a small volume of methanol then with water. After drying under vacuum at 70° C. and further purification by recrystallization from ethyl acetate the title compound was obtained as a white solid.
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].ClC(Cl)(Cl)C[O:66][C:67](Cl)=[O:68]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:5]([CH2:4][CH2:3][CH2:2][C:67]([OH:66])=[O:68])=[O:6])[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=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
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)CCCC(=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
Temperature: -20 °C
Reaction time: 2 h

Procedure:
875 mg of paclitaxel was dissolved in 6 ml of pyridine and 40 ml of dichloromethane. The solution was cooled at −20° C. Three hundred microliters of trichloroethylchloroformate (Troc) (at −20° C.) was added by portions of 100 microliters and the solution was kept at −20°C. for two hours. An additional 100 microliters of Troc was added and the solution was stirred at room temperature for 20 hours. The solvent was evaporated to dryness. The residue was dissolved in 10 ml of dimethylformamide with 1.36 g of glutaric anhydride and 40 mg of dimethylaminopyridine. The solution was stirred at 85° C. for 20 hours. The product was precipitated with 10 volumes of water. The white precipitate was collected on a sintered glass filter and dried. The dried product was then dissolved in 20 ml of methanol:acetic acid (9:1) and 0.5 g of zinc powder was added. The solution was stirred at room temperature for 30 minutes. Zinc was filtered and the filtrate was evaporated to a volume of about 2 ml. 70 ml of dichloromethane was added and the solution was washed twice with 30 ml of 0.01N HCl, once with 30 ml of sodium bicarbonate and once with 50 ml of water. The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated to dryness. This yielded 620 mg of a C7-glutaryl paclitaxel
Reaction SMILES: CO.[CH3:3][NH2:4].C(O[C:8]([C:10]1[C:11]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9])C>O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11]3[C:10]([C:8]([NH:4][CH3:3])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Solvent: O
Solvent: CO
Product: CNC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To the solution of methanol with 40% methylamine (30 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (1.5 g) obtained by by preparation example 1, and the solution was reacted at 25-30° C. for 1 hr. The reaction mixture was cooled at 20-25° C., added H2O (90 ml) and stirred for 0.5hr. The reaction mixture was filtered, washed with 25% aqueous methanol solution (10 ml), obtained a solid product. The solid product was dried in vacuo to obtain the desired compound (1.26 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1noc2c(C)cccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1noc2c(C)cc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 72.7 %

Procedure:
3,7-dimethylbenzo[d]isoxazole (Step 46.4) (2 g, 12.77 mmol) was dissolved in H2SO4 (5 mL), cooled down and stirred at 0° C. HNO3 (0.878 mL, 12.77 mmol) was slowly added and the resulting mixture was stirred at 0° C. for 1 hr. The reaction was diluted with water (60 mL) and extracted three times with CH2Cl2. The combined organic layers were washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting yellow solid was triturated with Et2O, filtrated off, washed with Et2O and dried to afford the title product (1.86 g, 9.29 mmol, 73% yield) as yellow solid. tR: 0.98 min (LC-MS 2); ESI-MS: 193 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17]I)[N:14]=[C:13]([NH:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17][N:33]([CH3:34])[CH3:32])[N:14]=[C:13]([NH:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.1 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 0.29 mmol) in tetrahydrofuran (2 mL) was added dimethylamine (730 μL, 2 M in THF, 1.5 mmol) and the reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration provided the crude amine (120 mg, 88%). A portion of the crude amine (26 mg) was purified by flash chromatography (38:2 dichloromethane:methanol to 37:3 dichloromethane-methanol) to provide 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-[(dimethylamino)methyl]-2-pyrimidinamine (15 mg). Rf 0.32 (37:3 dichloromethane:methanol); 1H NMR (CDCl3) δ 8.37 (d, 1H), 7.66 (m, 2H), 7.26 (m, 1H), 7.11 (t, 2H), 7.03 (d, 1H), 6.39 (s, 1H), 5.18 (d, 1H), 4.35 (m, 1H), 3.23 (s, 2H), 2.22 (s, 6H), 2.07 (m, 2H), 1.80–1.45 (m, 6H); MS m/z 465 (M+1); mp 68–75° C.
Reaction SMILES: O.[CH3:2][N:3]1[C:8](=[O:9])[CH2:7][C:6](=O)[NH:5][C:4]1=[O:11].O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[NH:5][C:4](=[O:11])[N:3]([CH3:2])[C:8](=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CC(=O)NC1=O
Solvent: O
Product: Cn1c(=O)cc(Cl)[nH]c1=O
Temperature: 80 °C
Yield: 71.6 %

Procedure:
Water (2.7 mL) is added dropwise to a suspension of 1-methylpyrimidine-2,4,6(1H,3H,5H)-trione (14.2 g, 100 mol) in POCl3 (95 mL) at 0° C. The reaction mixture is then heated at 80° C. for 5 hours. The resulting brownish solution is cooled, and POCl3 is evaporated under reduced pressure. The residue is treated with MeOH, and the obtained solid is recrystallized from ethanol to give 11.5 g product (Yield: 71.6%). m.p.=279-282° C. (dec) [Lit.2: 280-282° C.]. 1H NMR (400 MHz, DMSO-d6) δ3.10 (S, 3H), 5.90 (S, 1H), 12.4 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 85 %

Procedure:
1.6 g (4.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 4.5 hours with 1.1 g (15 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there were obtained 1.50 g (85%) of 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 250°-252°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:7].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH:44][CH2:45][CH3:46])[CH3:43]>C(Cl)Cl>[CH2:42]([N:44]([CH2:45][CH3:46])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][CH:15]=1)[CH3:43]
Reactant: COc1cccc(C(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 0.23 grams of acid (3.1b), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents with respect to the acid) and 1-hydroxy benzotriazol hydrate (1.2 equivalents) in anhydrous CH2Cl2 (2 ml) is stirred at room temperature for 30 minutes. A solution of diethylamine (1.5 equivalents) in anhydrous CH2Cl2 (8 ml) is then dropwise added. The obtained mixture is stirred at room temperature for 14 hours and washed in a first step with saturated aqueous sodium bicarbonate and in a second step with water. The organic phase is dehydrated with sodium sulphate, filtered and evaporated under vacuum. The residue that is recovered is purified by flash chromatography (ligroin/ethyl acetate 1/1 v/v). N,N-diethyl-4-(3′-methoxybenzoyl)benzamide (3.1c) is obtained. Yield: 98%. IR (nujol) (λ=cm−1) 1690 (C═O); 1H-NMR (CDCl3) δ 1.00-1.38 (m, 6H); 3.20-3.38 (m, 2H); 3.50-3.70 (m, 2H); 3.86 (s, 3H); 7.10-7.40 (m, 4H); 7.48 (d, 2H, J=8.4 Hz); 7.84 (d, 2H, J=8.4 Hz). Anal. calc. for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.11; H, 6.78; N, 4.49.