Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1)=[C:10]2[Cl:30].[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[C:33]1[CH3:39]>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:37]([C:36]3[N:32]([CH3:31])[C:33]([CH3:39])=[N:34][CH:35]=3)[OH:38])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ncc(C=O)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.9 mL, 2.25 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.009 g, 2.338 mmol, Intermediate 9: step c) in dry THF (12.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (359.6 mg, 2.897 mmol) in dry THF (5 mL) was added dropwise. The reaction was stirred for 10 minutes, then was moved into an ice bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the separated aqueous layer was extracted with EtOAc/THF 10:1. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude was triturated with EtOAc/ether 1:1 and filtered, rinsing with additional ether. The collected solids were purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (d, J=2.0 Hz, 1H), 8.24-8.22 (m, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 6.54 (d, J=0.7 Hz, 1H), 6.03 (s, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.49 (s, 3H), 2.35 (s, 3H); MS m/e 477.0 [M+H]+.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17]O.[OH-].[Na+]>CO>[C:2]1([C:1](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)C1OC1c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mechanically stirred mixture of 83.2 g benzalacetophenone (0.3m), 1000 ml methanol and 120 ml 15% hydrogen peroxide was added 100 ml 2N sodium hydroxide solution, while maintaining the temperature below 30° by external cooling. After completed addition, the mixture was left standing at room temperature for 20 min. The crystalline precipitate was filtered off, washed with water and recrystallized from methanol. There were obtained 59.6 g 1,3-diphenyl-2,3-epoxy-1-propanone; m.p. 90° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([OH:17])(=[O:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.CI.O>CN(C)C=O>[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:7]([O:17][CH3:1])=[O:16])=[CH:9][CH:10]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
Anhydrous potassium carbonate (4.7 g) is added to a solution of terephthalaldehydic acid (5.1 g) in anhydrous dimethylformamide (110 ml), and the mixture is stirred at room temperature for 10 minutes. Then, methyl iodide (2.5 ml) is added thereto, and the mixture is stirred overnight. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 4.7 g (84%) of methyl 4-formylbenzoate as crystals.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=508.4.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:23]1[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Yield: 185.9 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.6 g, 2.0 mmol), prepared according to Example 40, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.477 mmol, 2.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.059 g, 0.084 mmol) were combined in a 35-mL microwaveable vessel. Subsequently, potassium carbonate (1.0 M in water, 5 mL) and acetonitrile (5 mL) were added. The reaction vessel was then subjected to microwave irradiation at 140° C. for 20 min. The mixture was diluted further with EtOAc and the product was isolated via acid-base extraction to provide 0.3 g (50% yield) of 2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:22]
Reactant: CCc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccccc1CC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 2-ethylphenol (244 mg) in acetonitrile (20 ml) was treated with cesium carbonate (650 mg) and ethyl bromoacetate (0.221 ml) and the mixture stirred at 60° C. for 6 hours and then at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate; the suspension filtered and the title compound isolated by evaporation in vacuo of the filtrate as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:13][C:12](=[CH2:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:17]1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][C:12]2([CH2:14][O:17]2)[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OO1
Reactant: C=C1CC(COCc2ccccc2)O1
Solvent: ClCCl
Product: c1ccc(COCC2CC3(CO3)O2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxymethyl-2-methyleneoxetane (0.025 g, 0.13 mmol) in CH2Cl2 under N2 was cooled to −78° C. Then, dimethyldioxirane (0.5 M, 0.52 mL, 0.26 mmol) was added dropwise, and the reaction was stirred at −78° C. for 1 h. The solvent was then evaporated to give 2-benzyloxymethyl-1,5-dioxaspiro[3.2]hexane, which was dissolved in dry THF (2 mL). The solution was stirred under N2 and cooled to 0° C. A solution of 1H-tetrazole (0.01 g, 0.14 mmol) in dry THF (2.0 mL) was added. The reaction mixture was stirred at 0° C. for 3 h and was then warmed to room temperature, followed by removal of the solvent in vacuo. The resultant oil was purified by preparatory TLC on silica gel (CH2Cl2/MeOH 96:4). 4-Benzyloxymethyl-2-hydroxymethyl-2-(tetrazol-2-yl)oxetane was isolated as a clear oil was (32 mg, 88% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.34 (m, 5H), 5.23 (m, 1H), 4.69 (d, J=11.9 Hz, 1H), 4.63 (d, J=11.9 Hz, 1H), 4.40 (app d, J=12.6 Hz, 1H), 4.17 (dd, J=12.2, 8.7 Hz, 1H), 3.83 (dd, J=11.7, 2.2 Hz, 1H), 3.68 (dd, J=11.7, 2.8 Hz, 1H), 3.60 (dd, J=12.3, 7.2 Hz, 1H), 3.40 (dd, J=12.3, 7.6 Hz, 1H), 3.24 (app d, J=5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.4, 137.6, 129.1, 128.6, 128.4, 97.8, 76.8, 74.2, 71.0, 65.4, 30.2; MS (EI) m/z 149, 107, 91 (100), 77, 65.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:10]1[O:12][CH2:11]1.[OH-].[K+]>O>[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O:5][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(CCCO)OCCO
Yield: 95 %

Procedure:
A 500 ml five-neck flask equipped with gas inlet tube, thermometer, high-performance stirrer and reflux condenser with gas incineration is charged with 152 g (1 mol) of ethyl(3-hydroxypropyl)phosphinic acid (produced similarly to Example 13). Ethylene oxide is passed in at room temperature. A reaction temperature of 70° C. is set with cooling, followed by further reaction at 80° C. for 1 hour. The ethylene oxide takeup is 64.8 g. The acid number of the product is less than 1 mg KOH/g. 186 g (95% of theory) of 2-hydroxyethyl ethyl(3-hydroxy-propyl)phosphinate are obtained as colorless, water-clear liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)C(C)C)C>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[N:24][C:19]([C:18]([F:17])([F:30])[F:29])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a suspension of 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (37 mg, 0.12 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (26 mg, 0.12 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 70 mg, 0.13 mmol) in CH3CN (1.0 mL) was added (i-Pr)2EtN (32 mg, 0.25 mmol) at 20° C. The reaction mixture was stirred at 20° C. under argon for 15 h, then concentrated in vacuo. The residue was dissolved in EtOAc (15 mL). The organic solution was successively washed with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μ C18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with EtOAc to afford 54 mg (92%) of the title compound as a white solid. LC/MS (method B): retention time=1.91 min, [M+H]+=487.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[C:3]=1[CH2:22][OH:23].N1C=CC=CC=1.[Cl:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.O>[NH2:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([C:15]2[CH:16]=[C:17]([NH:21][C:33](=[O:34])[CH2:32][CH2:31][Cl:30])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[N:7]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc(-c2cc(-c3ccccc3O)nc(N)c2CO)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCCl)c2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a cold (0° C.) solution of 2-[6-amino-4-(3-aminophenyl)-5-(hydroxymethyl)-2-pyridinyl]phenol (0.100 g, 0.325 mmol) in THF (3 mL) including pyridine (0.028 mL, 0.34 mmol) was added 3-chloropropionyl chloride (0.043 g, 0.34 mmol). After being stirred for 30 minutes, the mixture was allowed to warm to room temperature and the stirring was continued for 2 hrs. The resulting mixture was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized with ethyl ether. The resulting solid was collected by filtration, washed with ethyl ether, and dried under reduced pressure to give N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-chloropropanamide as a pale yellow solid (0.072 g, yield 56%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([OH:16])[C:11](I)=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:26]([C:28]1[CH:42]=[CH:41][C:31]([CH2:32][N:33]2[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]2)=[CH:30][C:29]=1[F:43])#[CH:27].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[O:16][C:26]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][N:33]4[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]4)=[CH:30][C:29]=3[F:43])=[CH:27][C:11]2=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Cc2ccccc2)c(Cl)nc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cl)c(Cc5ccccc5)cc4o3)c(F)c2)C1
Reaction time: 16 h

Procedure:
In a sealed flask was combined 5-benzyl-6-chloro-2-iodopyridin-3-ol (1.50 g, 4.3 mmol), PdCl2(PPh3)2 (0.30 g, 0.43 mmol), copper(I) iodide (0.17 g, 0.87 mmol), N-ethyl-N-isopropylpropan-2-amine (6.1 mL, 35 mmol), methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (1.2 g, 4.8 mmol) and DMF (10 mL, 129 mmol). The flask was flushed with argon, sealed and placed in an oil bath for 16 h at 80° C. The reaction was concentrated to remove solvent, and the resulting black mixture was adsorbed onto silica. Flash chromatography (100% EtOAc) afforded a yellow oil that was further purified on a Varian HF Mega Bond Elut SCX column (eluted with 2M ammonia in MeOH). Trituration with of the resulting solids with ether afforded an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.83-7.90 (1H, m), 7.49 (1H, s), 7.27-7.40 (5H, m), 7.22-7.24 (1H, m), 7.12-7.19 (2H, m), 4.20 (2H, s), 3.72 (3H, s), 3.65 (2H, s), 3.52-3.59 (2H, m), 3.32-3.38 (3H, m); MS (ESI) m/z: Calculated: 464.1; Observed: 465.1 (M++1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:20].[CH3:21][NH:22][CH3:23]>>[ClH:20].[ClH:20].[CH3:21][N:22]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1)[CH3:23]
Reactant: CNC
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: Cl
Product: CC(C)N1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 15 and dimethylamine hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:14]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(CCCCCCCCCCBr)Nc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 94.7 g (0.357 mol) of 11-bromoundecanoic acid and 70 ml of thionyl chloride was heated with a 90° oil bath until gas evolution had essentially stopped. Excess thionyl chloride was distilled from the reaction mixture under aspirator vacuum. Toluene (50 ml) was added and this was also distilled under aspirator vacuum. The cooled reaction mixture was then added to a slurry of 78.0 g (0.715 mol) of 4-aminophenol in 500 ml of dioxane. After stirring for 30 min the mixture was filtered and the solid was washed with hot dioxane. The combined filtrates were concentrated and the residue was recrystallized from chloroform to give the end product as colorless crystals, mp 116°-117°.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Cl:40][CH2:41][CH2:42][N:43]=[C:44]=[O:45]>C1COCC1>[Cl:40][CH2:41][CH2:42][NH:43][C:44](=[O:45])[NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)NCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.19 mmol) in THF, 1-chloro-2-isocyanatoethane (60 mg, 0.57 mmol) was added at 80° C. Then the reaction mixture was stirred at room temperature overnight. The mixture was extracted with EtOAc, washed with brine, dried and concentrated to provide 6-(3-(2-chloroethyl)ureido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (80 mg, yield: 66.5%) without further purification. MS (M+H)+: 628.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][N:25]([O:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[S:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)(=[O:13])=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A mixture of 1,4-benzodioxan-6-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb 23, 1994; 60 mg; 0.253 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,4-benzodioxan-6-sulfonyl chloride (12 mg, 0.051 mmol) was added and the reaction was heated for an additional 30 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate (125 mg, 86%) as a white solid. HL-NMR (chloroform-D3): 1.20 (m, 6H), 1.60 (m, 5H), 2.07 (m, 2H), 2.90 (m, 4H), 3.09 (b, 1H), 3.67 (m, 2H), 3.90 (m, 4H), 4.23 (m, 1H), 4.31 (m, 4H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.95 (d, 1H) 7.25 (m, 7H). MS(ESI): 655(M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][NH:12][CH3:13].[CH2:14]=O.Cl>C(O)C>[CH3:11][N:12]([CH3:14])[CH2:13][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1ccccc1F
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccccc1F
Yield: 86.2 %

Procedure:
1-(2-Fluorophenyl)ethanone (170 g, 1.23 mol), dimethylamine (137 g, 1.72 mol), and paraformaldehyde (55 g, 1.85 mol) were suspended in ethanol (500 mL), then concentrated HCl (3 mL) was added, and the mixture was heated to reflux overnight. The solvent was removed under vacuum. The residue was washed with EtOAc for 3 times to give 3-(dimethylamino)-1-(2-fluorophenyl)propan-1-one (207 g, 88%), which was used for the next step without purification. 1H NMR (CDCl3): δ=2.69 (s, 6H), 2.52 (m, 4H), 7.30 (m, 2H), 7.66 (m, 1H), 7.96 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:30][C:31]1[C:32](F)=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>>[Cl:30][C:31]1[C:32]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[N:33][CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was synthesized from N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (Aldrich) in a manner similar to that described for EXAMPLE 94, Step 3.