Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(CO)c(Cl)c1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(COCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c(Cl)c1

Procedure:
Using (2-chloro-4-methoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-methoxybenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxy propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3.[CH:24](=O)[CH3:25].[BH4-].[Na+].O>C(O)C>[CH2:24]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH3:25]
Reactant: COc1ccc2ccn3c(N)c(-c4ccccc4C)nc3c2c1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1c(-c2ccccc2C)nc2c3cc(OC)ccc3ccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.0 g of 3-amino-9-methoxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 26) in 100 ml of ethanol was added 3.0 ml of acetaldehyde, and the mixture was stirred at room temperature for 3 hours. After 3.3 g of sodium borohydride was added to the mixture and refluxed for 2 hours, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The crude crystal was recrystallized from petroleum ether/ethyl acetate to give 5.0 g of the title compound as colorless needles.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:21]3=[N:25][N:26]=[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]3[N:19]=[C:18]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[C:28]1([C:27]2[N:20]3[N:19]=[C:18]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[C:17]4[CH2:16][NH:15][CH2:24][CH2:23][C:22]=4[C:21]3=[N:25][N:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(OCc3ccccn3)nn3c(-c4ccccc4)nnc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nnc3c4c(c(OCc5ccccn5)nn23)CNCC4)cc1
Yield: 96.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of 3-phenyl-5-(pyridin-2-ylmethoxy)-8,9-dihydro-6H-1,2,3a,4,7-pentaazacyclopenta[α]-naphthalene-7-carboxylic acid tert-butyl ester (217 mg, 0.47 mmol) in dry dichloromethane (3 ml) at 0° C. under nitrogen. After 1 hour the volatiles were removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/ammonia (60:8:1) to afford the title amine (162 mg, 96%) as a colourless solid, m.p.=157-159° C. 1H NMR (360 MHz, d6-DMSO) δ2.92-2.96 (2H, m), 3.07 (2H, t, J=5.8 Hz), 3.84 (2H, s), 5.56 (2H, s), 7.36 (1H, dd, J=6.7, 4.9 Hz), 7.52-7.60 (4H, m), 7.87 (1H, td, J=7.8, 1.7), 8.23 (2H, dd, J=6.3, 1.9 Hz), 8.62-8.64 (1H, m). MS (ES+) m/e 359 [MH]+. Anal. Found C, 64.93; H, 5.31; N, 22.30. C20H18N6O.0.75 H2O requires C, 64.59; H, 5.29; N, 22.60%.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>O1CCCC1>[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CNC(N)=O
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 0.9 %

Procedure:
Prepared as described in General Procedure 1. To methyl urea (0.24 g) in tetrahydrofuran was added sodium hydride (22 mg of 60% in oil) and the reaction mixture stirred for 50 min at room temp. Dicyclohexyl carbamoyl chloride (0.8 g) was then added (ice bath cooling used during addition) and the mixture was stirred overnight. The reaction mixture was then added to 0.5 ml water, partially concentrated in vacuo and water (2 mL) and ethyl acetate (10 mL) was added. The non soluble material was removed by filtration and the organic layer collected and concentrated in vacuo. An aliquot of the crude was then dissolved in THF and purified by preparative LCMS to give the desired product (8 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([CH2:7][CH:8]([CH3:12])[C:9]([OH:11])=O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>O1CCCC1>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(CC(=O)c1cccc(F)c1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)C(C)CC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.10 g. of 3-(4-fluorobenzoyl)-2-methylpropionic acid (Example 2) in 20 ml. of tetrahydrofuran is added 1.62 g. of 1,1'-carbonyldiimidazole. The mixture is stirred at room temperature for one hour, then 1.66 g. of L-proline methyl ester is added and stirring is continued for 18 hours. The mixture is evaporated to dryness in vacuo and the residue is partitioned between dichloromethane and water. The organic layer is separated and washed successively with 1 N hydrochloric acid, water, sodium bicarbonate solution and saline, dried over magnesium sulfate and evaporated to dryness in vacuo giving the desired product as 1.98 g. of a gum.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[CH2:15][S:14]1.Cl>O1CCCC1>[F:9][C:2]([F:1])([F:8])[C:3]([CH:15]1[C:16](=[O:23])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][S:14]1)=[O:5]
Reactant: O=C1CSCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2CSC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 70.8 h
Yield: 82 %

Procedure:
Ethyl trifluoroacetate (3.67 g, 25.8 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with 25% sodium methoxide (6.46 g, 29.9 mmol) followed by a solution of isothiochroman-4-one (4.15 g, 25.3 mmol) in tetrahydrofuran (15 mL). The reaction was stirred at room temperature for 70.8 hours and treated with 3N hydrochloric acid (10 mL). The organic layer was collected, washed with brine, dried over MgSO4, concentrated in vacuo, and passed through a column of silica gel eluting with 40% ethyl acetate/hexane to give a brown solid (5.40 g, 82%): 1H NMR (CDCl3) 300 MHz 15.30 (s, 1H) 7.99 (d, J=7.9 Hz, 1H) 7.54 (m, 1H) 7.43 (m, 1H) 7.23 (m, 1H) 3.81 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:13]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:12][CH:11]=[CH:10][C:9]=1[O:21][CH3:22])(=O)=O.C(#[N:25])C>>[CH3:22][O:21][C:9]1[C:8]2[CH2:7][CH2:6][NH:25][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Reactant: CC#N
Product: COc1cccc2c1CCNCC2
Temperature: 100 °C

Procedure:
Dissolve 2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L) and split the mixture into two equal lots. In two separate runs, add concentrated aqueous NH4OH (3.5 L) and charge the solution to a pressure vessel (Parr apparatus). Heat the solution in a closed reactor to 100° C. over 20 min (internal pressure reaches about 100 psi), and maintain at 100° C. until the reaction is complete (about 1 h, HPLC monitored). Cool the reaction mixture to ambient temperature. Combine the two lots and remove the solvent in vacuo. Dissolve the residue in MTBE (3.5 L) and water (3.5 L). Adjust the pH to 6.5 using 2M aqueous NaOH or 1M aqueous HCl as appropriate (typically the pH is about pH=5.1 and the adjustment requires about 50 mL 2M aqueous NaOH). Discard the organic layer, adjust the aqueous layer to pH=13 using 50% NaOH (about 150 mL). Extract with MTBE (2×3.5 L), wash the combined organic layers with brine (3.5 L), dry over Na2SO4, filter and concentrate in vacuo to give the title compound as a crude yellow oil that solidifies upon standing (179.3 g). Use the material for the next step without further purification. Prepare an analytical sample by purification by two Kugelrohr distillations to give a clear oil that solidifies upon standing, mp 44.3-45.0° C. 13C NMR (300 MHz, DMSO-d6), δ 156.1, 144.4, 130.3, 126.2, 121.5, 108.9, 55.5, 48.2, 47.9, 39.9, 29.1; MS (ES+) m/z 163 (M+H)+; Anal. Calc'd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.28, H, 8.62; N, 7.86.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:7][CH2:6]1.Cl[C:21]1[C:22]2[C:29]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:31])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:21]2[C:22]3[C:29]([C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:7][CH2:6]1
Reactant: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Reactant: COCCN1CCN(CCc2ccccc2N)CC1
Product: COCCN1CCN(CCc2ccccc2Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)CC1

Procedure:
(4-((2-(2-(4-(2-Methoxyethyl)piperazin-1-yl)ethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized using 2-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)aniline and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone according to the general procedure A. A white solid was obtained. M.p.=192-193° C.; 400 MHz 1HNMR (DMSO-d6) δ 10.66 (s, 1H), 8.31 (s, 1H), 7.98-7.94 (m, 2H), 7.84-7.82 (m, 2H), 7.70-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.30-7.25 (m, 2H), 7.13-7.09 (m, 1H), 3.33 (t, J=6.0 Hz, 4H), 3.32 (s, 3H), 2.90 (d, J=8.0 Hz, 2H), 2.51-2.46 (m, 4H), 2.36-2.33 (m, 4H), 2.24 (bs, 2H); LCMS [M+H] 463.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5](N)=[CH:4][C:3]1=2.[H+].[B-](F)(F)(F)[F:23].N([O-])=O.[Na+]>O>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([F:23])=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1cc2c(cc1N)C(C)(C)CCC2(C)C
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(cc1F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In an ice bath, ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C, 150 mg, 0.55 mmol) was added 0.24 ml of HBF4 (48% solution in water), followed by a solution of NaNO2 (81 mg, 1.16 mmol) in 1 ml of water. The slurry was left in a refrigerator for 3 days. The reaction mixture was washed successively with ethyl acetate until TLC showed no UV visible spot at the baseline. The ethyl acetate layer was dried with MgSO4 and the solution was concentrated to an oil. The oil was further dissolved in 1 ml of toluene and the mixture was heated under reflux for 2 h. After the reaction cooled to room temperature, solvent was evaporated and the residue was passed through a column (silica gel, ethyl acetate/hexane 1/10) to give the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[F-].[K+]>CN1CCCC1=O>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Fc1ccccn1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1
Yield: 50 %

Procedure:
4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-piperidine (0.305 g, 1.0 mmol, prepared as described in Example 8b), 2-fluoropyridine (0.117 g, 1.2 mmol), and anhydrous potassium fluoride (0.174 g, 3.0 mmol) were heated to 150° C. in 3 mL N-methylpyrrolidinone for 52 hours. The warm reaction mixture was added slowly to a rapidly stirring mixture of aqueous NaOH/ice/methanol to give a tan precipitate. The solid was collected and washed with water. The solid was dissolved in methanolic hydrogen chloride and concentrated to dryness several times from methanol to give the hydrochloride salt of the title compound as a white solid (0.239 g, 0.5 mmol, 50%), mp 270° C. (decomp); MS(CI): 382 (M+H); NMR (300 MHz, DMSO-d6): 10.27(br s, 1H), 7.95-7.85(m, 2H), 7.39-7.33(m, 5H), 7.04-6.96(m, 5H), 6.85(br m, 1H), 4.47(s, 1H), 4.41(s, 2H), 4.20-4.00(br m, 1H), 3.66-3.30(m, 4H), 2.76(s, 2H), 2.20-2.04(m, 4H).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:22])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])[NH2:13])[CH3:3].[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:22])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])[NH:13][C:33](=[O:32])[C@H:34]([CH2:46][CH:47]([CH3:48])[CH3:49])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 18.6 g. of L-arginyl-L-proline N-ethylamide hydrochloride (Ex.1,1) and 7.2 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenylester in 30 ml. of dimethylformamide is allowed to stand for four days, warmed to 50° C. for a half hour and evaporated at reduced pressure and 40° C. to yield an oil. A solid product is obtained by chromatography over silica gel, eluting with chloroform with increasing percent of methanol. Fraction selection is made on the basis of analytical thin layer chromatography and the product obtained solid by precipitating from methanol with ethyl acetate and then by dropping a methanol solution into ethyl ether. The solid is dried at 40° C. and reduced pressure; [α]D25 -68.4° (c 1, methanol); ultraviolet in methanol λmax 257 E11 3.5.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 63, 114 mg, 0.24 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (105 mg, 90%) was a white powder: [α]23589=−23.03° (c=0.33 chloroform); EI-HRMS m/e calcd for C21H23Cl2N3O4S (M+H)+ 484.0859, found 484.0862.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[N:16]([O-])=[O:17].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([N:16]=[O:17])=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(N=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15.5 g (80 mmol) of ethyl N-methyl-N-phenylglycinate in 80 g of ice and 40 mL of conc.HCl was stirred at 0-5° while a solution of 6 g (87 mmol) of NaNO2 in 40 mL of water was added dropwise over 30 min. After stirring at this temp. for 1 hr, a solution of 27 g (250 mmol) of Na2CO3 in 150 mL of water was added dropwise with cooling. The green solid was collected, washed with cold water, extracted into CH2Cl2, passed thorugh silica with CH2Cl2 to remove an impurity, and the product eluded with 10% ethyl acetate/CH2Cl2 to give 14.7 g (66 mmol, 83%) mp 55-56° after washing with 10% ethyl acetate/hexane. Anal. C11H14N2O3 (222): Calcd.: C,59.45; H,6,35; N,12.60. Found: C,59.46; H,6.14; N,12.49. MS(FD) m/z 222. 1H NMR(CDCl3)δ: 7.8,broad s,2H,ArH; 6.69,d,2H,ArH; 4.22,q,2H,CH2 --O; 4.20,s,2H,CH2 --N; 3.23,s,3H,CH3 --N; 1.27,t,3H,CH3 --C.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1(C(OC(C)(C)C)=O)[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[O:15])[CH2:10][CH2:9]1>>[ClH:1].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[O:21][CH2:22][CH2:23][O:24]2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCCC2OCCO2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCCCC1OCCO1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HCl-dioxane (4 M, 5 mL, 20 mmol) was added to 4-(3-(1,3-dioxolan-2-yl)propyl) 1-tert-butyl piperidine-1,4-dicarboxylate (0.71 g, 2.07 mmol) and the reaction mixture was stirred at RT for 1.5 hours. The solvent was evaporated at reduced pressure. The crude material was used directly without purification.
Reaction SMILES: Br.[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[C:20](=[CH:25]N(C)C)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>CCO>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]2[N:9]=[C:8]([N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[N:10]=[CH:25][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N=C(N)N1CCOCC1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(N3CCOCC3)ncc2C1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a 500 ml round bottom flask charged with anhydrous EtOH (150 ml) under nitrogen at 0° C. are added morpholine-4-carboxamidine hydrobromide (10.50 g, 50 mmol), tert-butyl-3-[(dimethylamino)methylene]-4-oxo-1-piperidinecarboxylate (12.7 g, 50 mmol, 1.0 eq.), and potassium t-butoxide in t-butanol (11.0M, 100 ml, 100 mmol, 2.0 eq.). The resulting mixture is stirred at 75° C. for 16 hr. The solvent is evaporated under reduced pressure, and the residue is taken up in DCM (300 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue is purified by silica gel chromatography (Hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 321.1 (M++1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36]>>[Cl:36][CH2:35][CH2:34][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:29])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=2[CH3:30])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:32])[CH:17]=[CH:16][N:15]=1)([CH3:20])[CH3:21]
Reactant: ClCCBr
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O

Procedure:
The title product was prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 169g, 0.33 g) and 1-bromo-2-chloroethane using a similar method to that described for example 167e.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([O:17][CH2:18][S:19][CH3:20])=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([O:17][CH2:18][S:19]([CH3:20])=[O:26])=[O:16]
Reactant: CSCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)COC(=O)c1oc(-c2ccccc2)cc(=O)c1Br

Procedure:
A solution of methylthiomethyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (0.36 g) and m-chloroperoxybenzoic acid (0.22 g, 80% pure) in chloroform (5 ml) was stirred for 4 hours at room temperature, filtered, washed with sodium bicarbonate solution, and evaporated. The residue was recrystallised from ethyl acetate-petroleum ether 60°-80° C. to give the title product (mp 159° C.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](COCC[Si](C)(C)C)[N:10]=[C:9]2[O:23][CH3:24].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[O:23][CH3:24]
Reactant: COc1nn(COCC[Si](C)(C)C)c2ccc(C3OCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COc1n[nH]c2ccc(C3OCCO3)cc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To 940 mg (2.682 mmol) 5-(1,3-dioxolan-2-yl)-3-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 805 mg (13.41 mmol) ethane-1,2-diamine in THF (50 ml) were added 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF). The reaction mixture was heated to 50° C. for 3 h. After this time, 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF) were added again, and heating was continued for further 12 h until conversion was complete. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated, and the remaining solid was purified by chromatography on silica gel (cyclohexane/ethyl acetate gradient) to afford 556 mg (94% of th.) of the intermediate compound 5-(1,3-dioxolan-2-yl)-3-methoxy-1H-indazole [LC-MS (method 3): Rt=1.44 min; MS (ESIpos): m/z=211 (M+H)+]. This material was dissolved in ethanol (37 ml), treated with 1 N hydrochloric acid (9.4 ml) and heated to 90° C. for 30 minutes. After this time, the mixture was evaporated to dryness, and the crude aldehyde thus obtained was used in the next step without further purification.