Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:18]=[C:5]=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C=NCc1cccc(F)c1
Temperature: 25 °C
Yield: 110.8 %

Procedure:
To a solution of triphosgene (2.37 g, 8 mmol) in CH2Cl2 (48 mL) was added dropwise a mixture of 3-fluorobenzylamine (2.0 g, 16 mmol) and DIPEA (4.14 g, 32 mmol) in CH2Cl2 (32 mL) over 2 hours at 0 C under N2 atmosphere. After addition was complete, the mixture was refluxed for 1 hour and then cooled to ambient temperature. The mixture was washed with aq. KHSO4, brine, dried over Na2SO4, and concentrated to give 3-fluorobenzyl isocyanate as a yellow liquid (1.34 g, yield 100%), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C(N)(C)C.[CH2:25]([OH:27])[CH3:26]>>[CH2:25]([O:27][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH3:26]
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C(C)C
Reactant: CCO
Solvent: CC(C)N
Product: CCOC1=C(N(C(C)=O)C(C)C)C(=O)c2cnn(C)c2C1=O

Procedure:
6-Chloro-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione (3 grams prepared by a similar method to that described in Example III) and isopropylamine (3 grams) in ethanol (25 milliliters) were heated together under reflux for 10 minutes. On cooling the reaction mixture a yellow-orange solid crystallized out, which was filtered off and dried to yield 6-ethoxy-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione having a melting point of 154°-155° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]2=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=[C:7]2[O:6][N:5]=1)[CH3:3].CC(C1OC2C(=C(O)C=CC=2)N=1)C.Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:3][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc2cccc(O)c12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)c1nc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Temperature: 110 °C

Procedure:
A mixture of 3-(1-methylethyl)-1,2-benzisoxazol-4-ol and 2-(1-methylethyl)-1,3-benzoxazol-4-ol (Intermediate 40, 13 mg), was dissolved in DMF (2.0 mL) and 2-chloro-5-nitropyridine (11.6 mg, 0.073 mmol) was added, followed by potassium carbonate (30 mg, 0.22 mmol). The reaction mixture was heated under microwave irradiation at 110° C. for 1 hour. After the removal of the volatiles, the residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from 10/0 to 9/1, then 9/1, then from 9/1 to 8/2) to afford the title compound (8.7 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:10][CH2:9][CH:7]3[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]3)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (150 mg) was carefully added to the solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (0.3 ml) in DMF (2 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. for 1 hour. The mixture was poured into 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 463(MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12.[Li][N:25]=[N+:26]=[N-:27]>CN(C=O)C>[N:25]([CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12)=[N+:26]=[N-:27]
Reactant: [Li]N=[N+]=[N-]
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol), LiN3 (0.0213 g, 0.43 mmol), and DMF (1.5 ml) and heat at 90° C. for 3 hours. Cool, add ice and extract with ethyl acetate. Wash organic layer with 3× with water. Dry over anhydrous sodium sulfate and concentrate to a residue which yields after separation on silica gel with 20% EtOAC/hexanes, the titled compound (0.01 g, 34%). 1H NMR (CDCl3) 7.2 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.73 (s, 1H), 6.68 (s, 1H), 4.35 (s, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H) 2.55 (m, 1H), 2.25 (m, 1H), 1.7-1.2 (m, 5H). MS m/z 334 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:11])=[O:10])=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(Br)cc1Cl
Yield: 62.4 %

Procedure:
Prepared from 4-bromo-6-chlorobenzene sulfonyl chloride (5.0 g, 17.3 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.16 g, 17.3 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as an off-white solid (4.1 g, 10.8 mmol, 62%). δH (D-6 DMSO, 300K) 9.52 (1H, s), 8.05 (1H, d J 1.6 Hz), 7.72-7.63 (3H, m), 3.54 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 379.9 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16].Cl>ClCCl>[C:6]([C:2]1[NH:1][CH:5]=[C:4]([C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[CH:3]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc[nH]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 1-(1H-Pyrrol-2-yl)-ethanone (0.980 g, 8.98 mmol) in dichloromethane (10 mL), anhydrous aluminum trichloride (3.05 g, 22.9 mmol) were added and the suspension was vigorously stirred for 15 minutes. Trichloro-acetyl chloride (1.53 mL, 13.74 mmol) in 7 mL of dichloromethane was slowly added and the mixture was then refluxed for 3 hours. The reaction mixture was cooled and poured into an iced solution of 75 mL of HCl 2N and vigorously stirred for 2 hours. Organic layer was separated and then washed with a saturated solution of NaHCO3 (2×100 mL) and water (80 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 1.061 g of (46%) of the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)NCCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-phenyl-ethylamine
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].CN(C)C=O.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>CC(C)=O>[OH:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(C2CCCCC2O)C1=O
Temperature: 60 °C

Procedure:
A mixture of 128.1 g of 5,5-dimethylhydantoin (1 mol), 1 g of lithium chloride and 200 ml of dimethylformamide is stirred at 100° C in a 500 ml glass apparatus having a stirrer, thermometer, dropping funnel and reflux condenser. 100 g of cyclohexene oxide (1.02 mols) are added dropwise to this solution over the course of 120 minutes, whilst stirring. Thereafter the mixture is stirred for a further 5 hours at 125°-130° C. After cooling to about 60° C, the reaction mixture is filtered and is concentrated to dryness on a rotary evaporator at 70° C under a waterpump vacuum. Thereafter the residue is dried to constant weight at 90° C/0.1 Hg. 217.8 g of a yellowish, crystalline material (96.4% of theory) are obtained, and this can be recrystallised, for example from acetone. The purified product melts at 159°-161° C. Elementary analysis shows the following values:
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:38][C:28]1[CH:29]=[CH:30][C:31]([S:34]([O-:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 82.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and p-toluenesulfonic acid (0.52 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 4-methylbenzenesulfonate as a crystalline white solid (1.2 g, 82% yield).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A five liter reaction flask was fitted with a mechanical stirring apparatus, a condenser, an addition funnel, and a thermocouple. The reaction flask was flame dried, and then cooled under a nitrogen atmosphere to room temperature. Under a static nitrogen blanket the reaction flask was charged with 10-undecen-1-ol (468 g, 3 mol) and toluene (1 L) while stirring. The contents were cooled to −10° C. and phosphorus tribromide (270 g, 1 mol) was added dropwise. The temperature was maintained at −10° C. with the aid of a Jack-o-matic, and the reaction mixture was aged for one hour. The reaction mixture was subsequently quenched and washed with brine (1 L). The organic layer was removed, and the product was distilled to provide 11-bromo-undec-1-ene (boiling point 95° C. at a pressure of 10 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][C@H:17]3[CH2:36][N:21]4[C:22]5[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]4[CH2:19][CH2:18]3)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](NC(=O)C1(c3ccc(F)cc3)CCCC1)CC2

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and propyl [(7R)-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 435.
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([OH:35])CCCCC>>[C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:21][CH:22]([OH:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]([CH3:20])([CH3:19])[CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccccc1
Reactant: CCCCCCO
Reactant: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1
Product: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(O)c1ccccc1

Procedure:
A mixture of 11.45 parts of 4-phenylcarbamoyloxy-2,2,6,6-tetramethylpiperidine and 60 parts of styrene ocide in 60 parts of n-hexanol was heated under reflux conditions for 18 hours. The n-hexanol solvent and unreacted styrene oxide were removed by distillation under reduced pressure to yield a pale yellow crystalline solid. Purification by trituration with hot petroleum ether (b.p. 60°-80° C.) yielded 4-phenylcarbamoyloxy-1-[2'-hydroxy-2'-phenylethyl]-2,2,6,6-tetramethylpiperidine having a melting point of 186°-7° C. with the following elemental analysis by weight:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:30]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([CH:40]3[CH2:45][CH2:44][N:43]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]4[C:16](=[O:17])[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]4=[O:18])[CH2:42][CH2:41]3)[N:30]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(CCCCCCN4C(=O)c5ccccc5C4=O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6 mmol of 2-(6-bromo-hexyl)-isoindole-1,3-dione, 6 mmol of compound 5c and 3 g of potassium carbonate in 50 ml of dimethylformamide is stirred for 18 h at RT. After evaporating the solvent, the residue is partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated. The residue is purified by chromatography (ethyl acetate:hexane/4:1). M. p. 39-44° C.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=[CH:22][O:23][CH3:24])[CH2:12]1)=O)C1C=CC=CC=1.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC>>[CH3:24][O:23][CH2:22][CH2:21][CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:11][CH2:12]1
Reactant: COC=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Product: COCCC1CNc2ccccc2C1

Procedure:
The title compound is prepared in a manner analogous to that described in Example 1r) starting from 2.3 g of N-benzyloxycarbonyl-3(R,S)-(1-methoxyethen-2-yl)-1,2,3,4-tetrahydroquinoline: Rf (A)=0.40; FAB-MS: (M+H)+ =192.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:37])[CH2:24][N:25]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>C(O)C>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:23]([OH:37])[CH2:24][N:25]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)N(CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 8 h

Procedure:
To 18.3 g of 3',5'-dibenzyloxy-ω-(benzyl-t-butylamino)-acetophenone in ethanol were added 2 g of sodium borohydride. The reaction mixture was allowed to stand overnight. Some methanol was added and the solution was evaporated. To the residue was added water and 2-N sodium hydroxide solution and the water phase was extracted with ether. The ether phase was dried with magnesium sulphate. The ether was evaporated and an oil was collected, which crystallized on standing. M.p. 78°-79°C. The resulting 1-(3',5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol can be converted to the corresponding 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol by replacing benzyl groups with hydrogen in a known manner.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[I:22]CCI>C1COCC1.ClCCl>[Cl:1][C:2]1[C:3]([I:22])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Reactant: ICCI
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccccc1-c1nnc2cc(I)c(Cl)nn12
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (5.0 g, 15.6 mmol), prepared as in Example 25 Step c), and 1,2-diiodoethane (14 g, 50 mmol) in anhydrous THF (150 ml) was added via cannula to a stirred suspension of tris(dimethylamino)-sulfur (trimethylsilyl)difluoride (5.0 g, 18 mmol) in anhydrous THF (200 ml) at room temperature under nitrogen. After 18 h, the mixture was diluted with dichloromethane (400 ml) and washed sequentially with water (300 ml) and brine (200 ml). The organic layer was dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 3% methanol-dichloromethane, gave crude 6-chloro-3-(2-fluorophenyl)-7-iodo-1,2,4-triazolo[4,3-b]pyridazine (3.54 g) as a dark brown solid. This was subjected to the conditions described in Example 27 Step b) to give 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (1.32 g, 19% over two steps) as a yellow solid; 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 5.51 (2H, s), 7.28 (1H, dd, J=8 and 8 Hz), 7.37 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86 (1H, ddd, J=7, 7 and 1 Hz), 7.90 (1H, s), 8.68 (1H, s); MS (ES+) m/e 452 [MH]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][C:5]=1[N+]([O-])=O)[CH3:2].BrCC(Cl)=[O:17]>C(Cl)(Cl)Cl>[C:1]([NH:3][C:4]1[CH:10]=[CH:9][CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CCNc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
To a 100 mL flask was added 4-ethylamino-3-nitroaniline (1.1 g, 6.3 mmol) and anhydrous CHCl3 (45 mL). The solution was cooled to 0° C. prior to the addition of bromoacetyl chloride (0.62 mL, 7.5 mmol) and TEA (1.7 mL, 13 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over 1 h before the solvent was removed under reduced pressure. The crude material was chromatographed (SiO2, 0–40% EtOAc/Hex) to provide the intermediate acetanilide (540 mg, 1.8 mmol) as a red solid. To a solution of the intermediate in anhydrous DMF (25 mL) was added sodium acetate (1.41 g, 17.2 mmol). The suspension was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with EtOAc (25 mL), and the excess sodium acetate was removed by filtration under reduced pressure. The filtrate was concentrated under reduced pressure to provide the title compound (420 mg). 1H-NMR (CDCl3): δ 8.13 (1H, br s), 8.11 (1H, d), 7.90 (1H, br s), 7.79 (1H, dd), 6.80 (1H, d), 4.68 (2H, s), 3.33 (2H, m), 2.21 (3H, s), 1.35 (3H, t); MS(ESI): 282 (MH+).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1>O1CCOCC1.C(O)C>[ClH:1].[NH:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:5]2[C:4](=[O:3])[NH:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:6]=2)[CH2:18]1
Reactant: COc1ncc(-c2ccncc2)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1[nH]cc(-c2ccncc2)cc1N[C@@H]1CCCNC1
Temperature: 80 °C

Procedure:
A solution of HCl in dioxane (20 mL) was added to (R)-tert-butyl 3-((6-methoxy-[3,4′-bipyridin]-5-yl)amino)piperidine-1-carboxylate (1.00 g, 2.60 mmol) in ethanol (10 mL). The mixture was heated at 80° C. for 12 h in a sealed tube. After cooling to room temperature the mixture was concentrated and the crude residue was triturated with diethyl ether to afford 0.60 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 12.29 (br s, 1H), 9.30-9.50 (m, 1H), 8.90-9.10 (m, 1H), 8.76 (br s 2H), 8.32 (br s, 2H), 7.74 (s, 1H), 7.04 (s, 1H), 5.65-5.90 (m, 1H), 3.20-4.10 (m, 5H), 2.60-2.90 (m, 1H), 1.60-2.05 (m, 3H); MS (ES) m/z 271 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=2)=[N:12][C:5]2[O:6][CH2:7][C:8](=O)[N:9]([CH3:10])[C:4]=2[CH:3]=1.B.C1COCC1.Cl>C1COCC1>[Br:1][C:2]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=2)=[N:12][C:5]2[O:6][CH2:7][CH2:8][N:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2nc3c(cc2Br)N(C)C(=O)CO3)ccc1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3c(cc2Br)N(C)CCO3)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
To the stirring solution of 7-bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (595 mg) and THF (15 mL) under argon was added BH3.THF (5.1 mL, 1N solution in THF) dropwise for 20 min. After 12 h, the reaction mixture was cooled in ice-bath and transferred 1N aq. HCl (16 mL). Subsequently, cooling bath was removed and heated at 80° C. for 1 h. The reaction mixture was concentrated, basified with aq. NaHCO3 solution and extracted with EtOAc (2×125 mL). Workup of the combined organic layers followed by flash column chromatographic purification (Combiflash® companion System® with RediSep® silica gel column 24 g and 30-50% EtOAc/hexanes eluting solvent) provided 450 mg of 7-bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.45-7.32 (m, 2H), 7.21 (s, 1H), 7.13 (dd, J=9.8, 8.5 Hz, 1H), 4.59-4.21 (m, 2H), 3.47-3.25 (m, 2H), 2.88 (s, 3H), 2.25 (d, J=1.9 Hz, 3H). 19F NMR (282 MHz, DMSO-d6) δ −118.92 (m).