Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH2:32][CH2:33]5)[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(O)CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
1-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-2-methyl-propan-2-ol was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-[4-(3-amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol (89.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.117 g, 68%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.22 (t, J=8.2 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.96 (dd, J=8.1, 1.3 Hz, 1H), 6.88 (s, 1H), 6.59 (dd, J=8.1, 1.7 Hz, 1H), 3.29-3.23 (m, 4H), 3.10 (s, 3H), 2.87-2.81 (m, 4H), 2.42 (s, 2H), 1.22 (s, 6H). MS=521 (MH)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccco2)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b) (140 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. (Bromomethyl)benzene (170 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH (aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). Yield 35%. MS M+H calculated 372.4, found 372.0.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:28])[CH3:27]>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)NCCCC(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CC(=O)NCCCC(=O)[O-]

Procedure:
According to the method of the preceding example, there are obtained, starting from 3.36 g of apovincamine and 1.45 g of 4-acetamidobutyric acid, 4.4 g of a product, having melting point of 128° C. and insoluble in water and alcohol. The apovincamine content of the salt is 56%.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:59][C:60]3[S:61][CH:62]=[CH:63][N:64]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.25 h

Procedure:
Procedure-C: 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (1 equi) (obtained in step III) and HATU (1.5 equi) was dissolved in DCM. To this solution was added DIPEA (2 equi.) and stirred for 15 minutes followed by addition of 2-aminothiazole (1 equi.) and continued to stir over night at room temperature. Reaction mixture was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38]>>[C:37]([CH2:39][C:40]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)=[O:41])#[N:38]
Reactant: N#CCC(=O)O
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: Cl
Product: N#CCC(=O)N1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and cyanoacetic acid, (Aldrich, Cat. No. C88505), LCMS (M+H)+: m/z=551.2.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:30](=[O:31])[CH2:29][CH2:28][C:25]3[CH:26]=[N:27][C:22]([C:21]([F:20])([F:33])[F:34])=[CH:23][CH:24]=3)[CH:15]=2)[N:10]=1
Reactant: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(C(F)(F)F)nc1)Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the product of Step B (307 mg, 1.2 mmol), the product of Step E (404 mg, 1.2 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 10 mL methylene chloride was added 4-dimethylaminopyridine (222 mg, 1.8 mmol) followed by 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCl (349 mg, 1.82 mmol). The resulting mixture was stirred at r.t. for 3 days. The solvent was removed under vacuum and residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate/triethylamine (1:7:0.1) to afford the product, MS: m/z 455 (MH+), as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[F:27])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:27])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of the nitro compound 119 (3.05 g, 7.93 mmol) in MeOH/THF (50 ml/50 mL) was added NiCl2×6H2O (3.77 g, 15.86 mmol) and NaBH4 (1.18 g, 31.73 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 2 M HCl. The acidic solution was then made basic with aqueous ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5, 9:1) to afford title compound 120 (2.00 g, 71% yield) as a yellow solid. MS (m/z): 355.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N+:9]2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99877.6 %

Procedure:
To a stirred solution of the crude intermediate 2-(4-chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile 1-oxide (23 g, 0.06 mmol) in chloroform (230 mL) was added phosphorus trichloride (23 mL) and the reaction mixture was then heated at 60° C. After 2 h, the reaction was cooled to RT and ice-water added (ca. 200 mL). The organics were extracted into DCM (3×200 mL), dried (Na2SO4) and concentrated in vacuo to give (v) (20.3 g, 92%), which was used unpurified in subsequent steps. ESI-MS m/z calculated for [M+H]+: 339.1. found: 339.0. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.92-7.81 (m, 2H), 7.69-7.57 (m, 3H), 2.42-2.29 (m, 1H), 1.14-1.03 (m, 2H), 0.82-0.72 (m, 2H).
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.[CH2:17]([O:24][C@H:25]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:28]([CH3:47])[O:27][C@@:26]1([CH2:49][P:50](=[O:57])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:24][C@H:25]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:28]([CH3:47])[O:27][C@@H:26]1[CH2:49][P:50](=[O:57])([O:51][CH2:52][CH3:53])[O:54][CH2:55][CH3:56])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(C[C@@]1(O)O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCOP(=O)(C[C@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
Boron trifluoride diethyl etherate (0.079 mL, 0.644 mmol, commercially available from Sigma Aldrich) and triethylsilane (0.103 mL, 0.644 mmol, Sigma Aldrich) were added to a stirred solution of diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.251 g, 0.429 mmol) in acetonitrile (2 mL) at 0° C. under an argon atmosphere. The reaction mixture was then stirred at 0° C. for 5 h. The reaction mixture was next partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (30 to 100% EtOAc/hexanes gradient) to give diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (0.220 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ ppm 1.14 (d, J=6.26 Hz, 3 H) 1.26 (td, J=7.04, 1.96 Hz, 6 H) 1.92 (td, J=15.75, 9.78 Hz, 1 H) 2.29 (ddd, J=19.95, 15.36, 1.47 Hz, 1 H) 3.53 (q, J=6.39 Hz, 1H) 3.56-3.70 (m, 4 H) 3.98-4.11 (m, 4 H) 4.63-4.77 (m, 4 H) 4.97 (dd, J=11.44, 1.86 Hz, 2 H) 7.26-7.39 (m, 15 H).
Reaction SMILES: ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.CC(C)(OC([N:26]([CH2:51][C:52]1[O:53][CH:54]=[CH:55][CH:56]=1)[CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30])=O)C>>[O:53]1[CH:54]=[CH:55][CH:56]=[C:52]1[CH2:51][NH:26][CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1ccco1
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCNCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)amino]-1-oxopropyl]hydrazide (25) was prepared in the same manner as 8-chlorodibenz-[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylmethyl)amino]propylhydrazide, monohydrochloride (18), as described above in Example 18, on a 0.37 mmol scale from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)amino]-1-oxopropyl]hydrazide (24), prepared as described above in Example 24, to yield 0.14 g (78%) of product. Analysis calculated for C22H21N4O4Cl.HCl. 0.25 H2O (M.W. 481.86): C, 54.84; H, 4.71; N, 11.63. Found: C, 54.56; H, 4.60; N, 11.33.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:22](Cl)([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23]>O1CCCC1>[C:7]([N:6]([C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23])[C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)(C)C

Procedure:
To a stirred solution of 2-nitro-N-tert-butylaniline (37 g) and triethylamine (35 ml) in tetrahydrofuran (400 ml) was added dropwise a solution of ethoxalyl chloride (25 ml) in tetrahydrofuran (50 ml). The mixture was then brought to reflux temperature for 8 h. The solvent was removed by evaporation, and the residue was partitioned between ether (300 ml) and water (500 ml). The organic phase was washed twice with water, dried over Na2SO4 and evaporated. This left the title compound as light yellow crystals, m.p. 73°-74° C.
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][NH2:20])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][N:20]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:16]=[CH:17][CH:18]=1
Reactant: NNc1cccc(Cl)c1
Reactant: OC1=NCCCCC1
Agent: COC
Solvent: CC(=O)O
Product: Clc1cccc(NN=C2CCCCCN2)c1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
35 G (0.28 mole) of caprolactim-methyl-ether were added dropwise over the course of 15 minutes at 5°C, while stirring and cooling, to a solution of 36 g (0.25 mole) of 3-chlorophenylhydrazine in 250 ml of glacial acetic acid; the red-brown clear solution was kept at 0° to 5°C for a further 2 hours and then for 2 hours at 20°C and excess glacial acetic acid was distilled off in a water-pump vacuum. On fractional distillation in vacuo of the residue which remained, 56 g (94.3% of theory) of caprolactam-(3-chlorophenylhydrazone) were obtained; it was a light viscous oil of boiling point 215° to 220°C/3 mmHg, which solidified to crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), 3-amino-5-methyl-1H-pyrazole (6.0 g, 62 mmol) and N,N-diisopropylethylamine (9.20 ml, 53 mmol) in 1-butanol (80 ml) was heated at 85° C. for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compound (10.8 g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+.
Reaction SMILES: OO.S([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15])(O)(=O)=O.Cl.Cl.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[NH2:30])[CH2:19][CH2:20][CH3:21].N>O.C(O)C>[Cl:15][C:9]1[C:8](=[O:7])[CH:13]=[CH:12][C:11](=[N:14][C:27]2[CH:28]=[C:23]([O:22][CH2:18][CH2:19][CH2:20][CH3:21])[C:24]([NH2:30])=[CH:25][C:26]=2[NH2:29])[CH:10]=1
Reactant: Nc1ccc(OS(=O)(=O)O)c(Cl)c1
Reactant: CCCCOc1ccc(N)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CCCCOc1cc(N=C2C=CC(=O)C(Cl)=C2)c(N)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
26 ml of 6% aqueous hydrogen peroxide solution are added to a solution of 180 mg (0.001 mol) of 4-amino-2-chlorophenol sulfate and 253 mg (0.001 mol) of 4-butoxybenzene-1,3-diamine dihydrochloride in 2 ml of water and 2 ml of ethanol, and the solution is adjusted to pH 9.5 with 20% aqueous ammonia. After stirring for 5 hours at room temperature, the precipitate formed is filtered off, washed with water and dried. A brown powder is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1cccc2c1C=C(C(=O)O)CO2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1CC(C(=O)O)CO2
Reaction time: 1 h

Procedure:
A mixture of 5-methoxy-2H-1-benzopyran-3-carboxylic acid (12.25 g, prepared in a similar manner to that described above), 10% palladium-on-carbon catalyst (3 g) and ethanol (250 ml) was hydrogenated at 1 atmosphere for 1 hour. Hydrogen uptake was slow, so further catalyst (3 g) was added, and hydrogenation continued for 5 hours. The mixture was filtered and the solvent removed in vacuo to leave a semisolid which crystallised from 2-propanol to give a mass of pale yellow crystals which was broken up, collected by filtration, washed with ice-cold 2-propanol, dried in vacuo, ground to a powder, and redried in vacuo to give 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid as a buff powder (7.4 g), m.p. 147°-150° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[N:3]=1.[Cl:21][C:22]1[C:23]([N:30]2[CH2:35][CH2:34][NH:33][C@H:32]([CH3:36])[CH2:31]2)=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:21][C:22]1[C:23]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[CH3:20])[N:3]=3)[CH:32]([CH3:36])[CH2:31]2)=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(Cl)c(N2CCN[C@H](C)C2)n1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)C(C)C2)n1

Procedure:
Heat a mixture of 4-chloro-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (440 mg, 1.51 mmol), 1-(3-chloro-6-methoxy-pyridin-2-yl)-3-(R)-methyl-piperazine (400 mg, 1.66 mmol), and K2CO3 (230 mg, 1.66 mmol) in DMA at 120° C. for 16 hours. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound. 1H NMR (300 MHz, CDCl3): δ1.36 (m, 6H, 2×CH3); 1.70 (m, 1H, CH2CH2); 1.93 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 3.05 (m, 2H); 3.38 (m, 1H); 3.70 (m, 2H); 3.88 (s, 3H, OCH3); 3.90 (m, 2H); 4.35 (m, 2H); 4.70 (m, 1H); 6.232 (s, 1H); 6.30 (d, 1H, J=8.4 Hz); 7.12 (m, 2H); 7.46 (d, J=9.0 Hz, 1H); 8.00 (m, 2H).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12](N)=[O:13])=[O:8].S(=O)(=O)(O)[OH:22]>O.C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12]([OH:22])=[O:13])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(SC)ccc(C(=O)O)c1C

Procedure:
Sodium nitrite (2.4 g) was added dropwise to a stirred solution of 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) in a mixture of concentrated sulphuric acid (50 ml), water (40 ml) and glacial acetic acid (70 ml) whilst maintaining the temperature below 5° C. The mixture was stirred without cooling for 0.5 hours. The brown solution was recooled to 0° C. and water (200 ml) was added. The mixture was extracted with ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzoic acid (4.6 g) as a sticky orange solid NMR (CDCl3) 2.1(s,3H), 2.5(s,3H), 3.9(s,3H), 7.0(d, 1H), 7.85(d, 1H), 9.0(bs, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][CH:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH2:13]1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
To 6-t-butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (0.50 parts) in dichloromethane (10 parts) at ambient temperature was added pyridine (0.20 parts) followed by a solution of acetylchloride (0.20 parts) in dichloromethane (2 parts). After 1 hour at 20°-25° C. less than 2% starting material remained by GLC analysis. The reaction mixture was then washed with water, dried over magnesium sulphate and evaporated to give 4-acetoxy-6-t-butyldimethylsilyloxymethyltetrahydro pyran-2-one (0.6 parts).