Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(O[C:11]([CH:13]=[CH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)=[O:12])C2C=CC=CC=2N=N1.CCN(CC)CC.CN([P+](O[N:43]1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[NH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[NH:43][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][C:11](=[O:12])[NH:59][CH2:60][C:61]2[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=2)=[CH:24][CH:23]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCc1cccnc1
Reactant: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)c1ccc(C=CC(=O)NCc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred solution at room temperature of VIII (140 mg, 0.68 mmol) in anhydrous DMF (5 ml) under nitrogen were added Et3N (104 μl, 0.75 mmol) and BOP reagent (331 mg, 0.75 mmol), respectively. After 30 min, a solution of 3-(aminomethyl)pyridine (90 μl, 0.88 mmol) or R1R2NH (1.2–1.3 equiv.), Et3N (284 μl, 2.04 mmol) in anhydrous DMF (2 ml) was added dropwise. After 4 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4Cl, H2O and brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2:5/95→7/93) to afford the title compound IXb (185 mg, 0.62 mmol, 92% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ(ppm): 8.67–8.44 (m, 2H), AB system (δA=8.03, δB=7.55, J=8.4 Hz, 4H), 7.78–7.64 (m, 2H), 7.33–7.26 (m, 1H), 6.54 (d, J=15.8 Hz, 1H), 6.38 (bs, 1H), 4.61 (d, J=6.2 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)[CH3:12])=[O:7].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]2([O:28][CH:15]2[CH2:14]1)[CH3:19])[CH3:12])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCC(C(C)CCOC(=O)c2ccco2)CC1
Solvent: ClCCl
Product: CC(CCOC(=O)c1ccco1)C1CCC2(C)OC2C1

Procedure:
The procedure of Example 1 was followed for the epoxidation of 5.2g (0.02 mole) of furoic acid, 3-(4-methyl-3-cyclohexenyl)butyl ester using 4.2g (0.02 mole) of 85% m-chloroperbenzoic acid in 150 ml of methylene chloride. Obtained following distillation was 3.7g of pure furoic acid, 3-(3,4-epoxy-4-methylcyclohexyl)butyl ester as a clear, colorless liquid with a boiling point of 156°-161° C. (0.10mm). (See Table I).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]1[C:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26]3)=[CH:21][N:20]=[CH:19]1>>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[C:23]([C:22]5[O:18][CH:19]=[N:20][CH:21]=5)[CH:24]=4)[NH:28][C:27]=3[OH:32])=[N:7][CH:6]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: O=C1Cc2cc(-c3cnco3)ccc2N1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(-c5cnco5)cc34)nc2)CC1
Yield: 1 %

Procedure:
The title compound was prepared as described for Example 101 using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (described in: Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and 5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one. The crude product was purified on a silica gel column using chloroform/methanol/conc NH3(aq), (100:10:1), as the eluent followed by trituration in ethyl acetate. Yield: 1% of the title compound: MS (ES) m/z 441 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CN2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C(=O)O)c1cc(Cl)c2c(c1)C(=O)c1ccccc1CN2C
Yield: 79.7 %

Procedure:
Methyl 2-(5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepin-2-yl)propionate (2.0 g), chloroform (50 ml) and N-chlorosuccinimide (1.4 g) were treated in the same manner as described in Example 9 to obtain the desired compound (1.7 g) as a yellow oily material.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=2[C:38]([F:39])([F:40])[F:41])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc([N+](=O)[O-])ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(3.9 g, 17.5 mmol) in THF (35 ml) at ambient temperature was added 1.0 M lithium bis(trimethylsilyl)amide in THF (17.5 ml, 17.50 mmol, Aldrich) dropwise. The solution was stirred for 20 min. To the solution was added a solution of 2-(bromomethyl)-4-nitro-1-(trifluoromethyl)benzene (7.3 g, 25.7 mmol) in THF (10 ml). The resulting dark brown solution was stirred at ambient temperature for 4.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (125 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The phases were separated and the organic phase washed with saturated aqueous sodium hydrogen carbonate (25 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a brown oil (˜11 g). The residue was loaded in dichloromethane and purified on silica 100 g×2 using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (4.31 g); LCMS: (System 4) MH+=427, tRET=2.80 min.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:48]=O>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:42]2[C:41]3[C:45](=[CH:46][CH:47]=[C:39]([F:38])[CH:40]=3)[NH:44][CH:43]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccc(F)cc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 71.5 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (100 mg, 0.198 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (38.8 mg, 0.238 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 provided 91.5 mg of N-benzyl-2-[8,9-difluoro-4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.92 (d, 1H), 7.10-7.67 (m, 13H), 6.84 (m, 1H), 6.64 (m, 1H), 4.37-4.97 (m, 5H), 4.20 (m, 1H), 1.20 (m, 6H); MS 647.4 (M+1), 645.3 (M−1).
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])C1C=CC=CC=1.[CH2:19]([O:21][C:22](=[O:28])[CH:23](Br)[CH:24]([CH3:26])[CH3:25])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:28])[CH:23]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[NH:8]2)[CH:24]([CH3:26])[CH3:25])[CH3:20]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C

Procedure:
A mixture of 4-hydroxy-2-methylindole (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71%
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([NH2:7])=[O:6])[CH3:4].[O:8]=[CH:9][CH2:10][CH2:11][C:12](OCC(C)C)=O>>[O:6]=[C:5]1[C@@H:3]([CH3:4])[N:2]2[C:9](=[O:8])[CH2:10][CH2:11][C@H:12]2[NH:7]1
Reactant: CC(N)C(N)=O
Reactant: CC(C)COC(=O)CCC=O
Agent: Cl
Product: C[C@@H]1C(=O)N[C@@H]2CCC(=O)N12

Procedure:
DL-Alaninamide hydrochloride (6.9 g, 0.055 mol) and isobutyl 4-oxobutanoate (7.3 g, 0.046 mol) were reacted together according the procedure of Example 2 to give the title compound, 1.7 g (24%), m.p. 84°-86°. NMR (DMSO-d6): deltaH =8.55 (bs, 1H, NH); 5.20 (t, J=5 Hz, NCHNH); 3.92 (q, J=6.5 Hz, 1H, CHCH3); 2.82-1.50 (c.a., 4H, CH2CH2); 1.17 (d, J=6.5 Hz, 3H, CHCH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 111 (M--CHNO+, 98 (M--C3H4O)+.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.85 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:19]([O:21]C)=[O:20].[I-].[Li+].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc2cc(NC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
Methyl N-(3,4-Dichlorobenzyl)-5-acetylaminoindole-2-carboxylate (88 mg) and lithium iodide (300 mg) were dissolved in pyridine and heated at reflux for 8 hours, then cooled to room temperature and poured into 2M HCl and extracted with diethyl ether. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography using DCM-2% methanol as eluent to give the desired end product as a white solid (19 mg, 22%), mp 245-246°; NMR δ(CD3SOCD3) 2.02 (s, 3H), 5.82 (s, 2H), 6.90 (d, 1H), 7.20-7.55 (m, 5H), 8.02 (s, 1H), 9.83 (s, 1H); M/z(+) 377 (MH+), 278.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>O>[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: Fc1cccc(F)c1Nc1cc(Cl)nn2ccnc12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3c(F)cccc3F)c3nccn3n2)CC1
Reaction time: 24 h

Procedure:
To crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine (0.186 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000 mg, 8.77 mmol). The mixture was allowed to melt at 160° C. for 24 hrs. The melt was then cooled, water was added, followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and the resulting residue purified by reverse phase preparative HPLC to provide 50.6 mg (46%) of the titled compound as a TFA salt. LC/MS, m/e 359 (M+1). HPLC Rt, 1.7 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min. Examples prepared in a similar manner are indicated in Table 2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(F)cc1)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)NC1CCNCC1
Yield: 90.6 %

Procedure:
To a solution of N-(1-benzylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (3.0 g) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added palladium on carbon (10% w/w, 50% wet, 0.6 g), and the mixture was hydrogenated under atmospheric pressure of hydrogen for 8 hours. The catalyst was filtered off, and the solvents were evaporated under reduced pressure to give a residue, which was triturated with diisopropyl ether to give N-(piperidin-4-yl)-N′-(4-fluorophenyl)urea (1.97 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:16]=2)=[N:2]1.N1C=CC=CC=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].[OH-].[NH4+]>>[NH:2]1[C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:43](=[O:45])[CH3:44])[CH2:26][CH2:25]2)=[N:4][CH:5]=[N:1]1
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CCOc2cccc(-c3n[nH]c4ccc(-c5ncn[nH]5)cc34)c2)CC1
Reaction time: 2 h
Yield: 8.8 %

Procedure:
1-(5-(1H-1,2,4-triazol-3-yl)(1H-indazol-3-yl))-3-(2-piperazinylethoxy)benzene (0.066 g, 0.169 mmol) was stirred with pyridine (0.50 mL, 6.18 mmol), triethylamine (0.10 mL, 0.717 mmol) and acetic anhydride (0.10 mL, 1.06 mmol) at ambient temperature. After 2 h, ammonium hydroxide (0.50 mL) was added and the mixture stirred for 1 h. The mixture was evaporated and gave the title compound (0.0064 g, 9% yield). 1H NMR (CD3OD) δ 8.71 (s, 1H), 8.35 (s, 1H), 8.08 (dd, 1H), 7.66 (d, 1H), 7.61 (dt, 1H), 7.55 (m, 1H), 7.44 (t, 1H), 7.01 (m, 1H), 4.25 (t, 2H), 3.58 (dt, 4H), 2.85 (t, 2H), 2.60 (dt, 4H), 2.08 (s, 3H). ES-MS (m/z) 432 [M+1]+
Reaction SMILES: [I:1]I.[I-].[K+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15].[NH:16]1[CH2:21][CH2:20][CH2:19][N:18]=[C:17]1[SH:22]>O.CO>[IH:1].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:22][C:17]2[NH:18][CH2:19][CH2:20][CH2:21][N:16]=2)=[C:7]1[CH3:15]
Reactant: II
Reactant: Cc1cc2ccccc2n1C
Reactant: SC1=NCCCN1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(SC2=NCCCN2)c2ccccc2n1C
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of iodine and 20 g of potassium iodide in 100 ml water is added dropwise to a mixture of 7.25 g of 1,2-dimethylindole in 30 ml of methanol and 5.8 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol in 120 ml of warm methanol. The reaction mixture is stirred for 2 hours at room temperature. The crystalline precipitate formed was filtered and recrystallized from a mixture of methanol and ethyl acetate to yield 1,2-dimethyl-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 246° (with decomposition).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:12][CH:10]([CH2:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH3:11]
Reactant: CC(=O)C=CCC(C)CC(C)C
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)CC(C)CCCC(C)O
Temperature: 170 °C
Reaction time: 3 h

Procedure:
64 g of the foregoing ketone are hydrogenated in a stirring autoclave in the presence of 6 g of copper chromite and under 40 bar hydrogen pressure. The temperature is firstly brought to 140° C. When the hydrogen absorption slows down (after 3 hours), the autoclave is heated to 170° C. and held for 3 hours between 165° C. and 170° C. After cooling down to 25° C., the catalyst is filtered off under suction and the filtrate is distilled. There are obtained 56 g (85.4%) of chemically pure 2,4-dimethyl-nonan-8-ol.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[NH:9][C:8]1([CH3:14])[CH3:13]>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]1[O:11][C:10](=[O:12])[NH:9][C:8]1([CH3:14])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)NC(=O)OC1CO
Solvent: c1ccncc1
Product: CC1(C)NC(=O)OC1CCl
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Thionyl chloride (0.13 ml, 1.72 mmol) was added to a mixture of 5-(hydroxymethyl)-4,4-dimethyloxazolidin-2-one (50 mg, 0.34 mmol) in pyridine (1 mL) at −20° C. The mixture was allowed to stir for 15 minutes and then warmed to 60° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford 5-(chloromethyl)-4,4-dimethyloxazolidin-2-one. 1H NMR (500 MHz, CDCl3) δ 6.20 (br s, 1H), 4.38-4.35 (m, 1H), 3.75-3.70 (m, 1H), 3.62-3.57 (m, 1H), 1.42 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][CH2:17][C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nnnn2C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 315 mg 4-[(S)-2-tert-Butoxycarbonylamino-4-(1-methyl-1H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane were added 0.5 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 0.41 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13](Cl)[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:34]=[CH:35][C:36]([C:13]3[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]4[N:7]=[C:8]5[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=[CH:9]5)=[C:5]4[N:14]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 21 %

Procedure:
1 g (2.9 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-2), 1.09 g (2.9 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 322 mg (0.28 mmol) tetrakis(triphenylphosphine)palladium and 886 mg (8.4 mmol) sodium carbonate in 30 mL dioxane and 4.2 mL water were heated over night at 105° C. The reaction mixture was poured on water/dichloromethane and vigorously stirred for 30′. The organic phase was separated, washed with brine, dried, filtered, and the solvent was evaporated. The residue was purified by HPLC yielding 346.4 mg (20.6%) of the title compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1[O:1][CH2:2][CH2:3][CH2:4][CH:5]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dihydro-2H-pyran (500 mg, 5.94 mmol) in THF (10 mL) was brought to −78° C. followed by the addition of tert-butyllithium (12.2 mL, 20.8 mmol, 1.7 M in pentane). The resulting yellow solution was brought to 0° C. and stirred for 15 min. The reaction was then cooled to −78° C. and tributyltin chloride (4.8 mL, 17.8 mmol) was slowly added. The reaction was monitored by TLC. Upon completion by TLC, water was added (20 mL) to the reaction. The organic phase was separated, washed with water, dried over MgSO4, concentrated and chromatographed on silica gel using hexanes (500 ml hexanes and 0.5 mL triethylamine). The title compound was obtained as a colorless oil. MS m/z: 375(M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:6]1[N:2]([CH3:1])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccn1C
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a dry flask is added methyl 1-methyl-1H-pyrrole-2-carboxylate (12.0 g, 86.4 mmol) and 150 mL of dry CH2Cl2, and the flask is wrapped in foil and purged with nitrogen. N-Bromosuccinimide (16.2 g, 90.7 mmol) is added in one portion and the mixture is stirred at rt for 0.5 h. The reaction mixture is washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Fractional distillation gives 12.0 g of methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate as a yellow oil (64% yield). MS for C7H8NO2Br (ESI) (M)+ m/z 217.1.