Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: CCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.37 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-2-(napthalen-2-yloxy)ethylamine, solid, m.p. 105° C., (yield 0.64 gm, 87.6%).
Reaction SMILES: CS(C)=O.[NH2:5][C@@:6]1([C:26]#[N:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-:29].[K+].[K+].OO>O>[NH2:5][C@@:6]1([C:26]([NH2:27])=[O:29])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23]
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reaction time: 0.5 h
Yield: 324.1 %

Procedure:
To a dimethyl sulfoxide (1.2 mL) solution containing 303.0 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 35.5 mg of potassium carbonate was added under cooling in water bath (13° C. approximately). Subsequently, 0.2 mL of 30 wt % hydrogen peroxide was added thereto and stirred for 30 min. After stirring for 67.5 hrs at room temperature, 3 mL of water was added to the reaction solution and the precipitated solids were filtered and washed with 1.2 mL of water. The resulting solids were dried under reduced pressure at room temperature to obtain 313.2 mg of (1R, 2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a) as a colorless solid.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:9][N:8]([C:4]2[CH:3]=[C:2]([CH3:10])[CH:7]=[CH:6][CH:5]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(C)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of m-tolylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of a 50% pyridine in ethanol. The resulting oil was purified by flash chromatography to yield the named product as a solid (m.p. 46.5° C.-47.5° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38](=N)[NH:39][NH2:40])[N:33]=1>ClCCl.C(O)CCC>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:34]3[N:33]=[C:32]([CH3:31])[CH:37]=[CH:36][N:35]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1ccnc(C(=N)NN)n1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.250 g, 0.859 mmol) was dissolved in dichloromethane (DCM) (2.147 ml) and triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added. The solution was left to stir at room temperature under argon for 18 hours. 4-Methyl-2-pyrimidine carboximidohydrazide (I99) (0.156 g, 1.031 mmol) was dissolved in 1-butanol (2.147 ml) and this was added to the reaction mixture and this was left to stir under argon for a further 60 minutes. The dichloromethane was removed under reduced pressure and the reaction mixture was left at reflux for 4 hours. The solvent was removed under reduced pressure to afford a crude product of 0.690 g. The crude material was purified by flash chromatography (Biotage Isolera 4, 50 g cartridge) with a gradient of methanol 0-10% in Dichloromethane. The solvent was removed under reduced pressure to afford 0.223 g of material which was further purified using MDAP. The solvent was removed under reduced pressure to afford 0.090 g of crude material that was dissolved in methanol and loaded onto a 5 g SCX column. The column was washed with methanol and the desired compound was eluted off using 2M ammonia in methanol. The solvent was removed under reduced pressure to afford the purified product in 0.075 g.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of 2-amino-2-methyl-propan-1-ol (104.5 g, 1.17 moles) in CH2Cl2 (400 ml) under N2 was dropwise added in 30 minutes with a solution of 4-methoxybenzoyl chloride (100 g, 0.59 moles) in CH2Cl2 (500 ml), keeping the temperature at about 8° C. with water/ice. After 3 hours under stirring the precipitate was filtered over celite and washed with CH2C2. The organic phase was stirred under N2 at 2° C. and dropwise added with thionyl chloride (123 ml, 1.77 moles), keeping the temperature below 10° C. At the end of the dropping the reaction mixture was stirred overnight, then concentrated under vacuum. The residue was taken up in 5% HCl and twice extracted with ethyl ether. The extracts were in turn extracted with 5% HCl. The aqueous phase was alkalinised with concentrated NaOH and extracted three times with ethyl ether, then anhydrified and concentrated under vacuum. The crude was distilled at 95-98° C. (30 Pascal) to give 106.43 g of the title compound (yield: 87.6%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([N:26]=[N+:27]=[N-:28])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N=[N+]=[N-])cc(-n2cnc3ccccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a solution of of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (EXAMPLE 306 Step B) (55.8 mg, 0.16 mmol) in DMF (1 mL) was added sodium azide (16 mg, 0.24 mmol) and the mixture was heated at 80° C. for 7 h. It was cooled and diluted with EtOAc, then the organic layer was washed with H2O followed by brine. The organic extract was dried over Na2SO4, and the crude material was purified by flash chromatography using 1:3 EtOAc:hexane to yield 48.8 mg of the title compound. Mass spectrum 357.1 (CI, M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:4]1.C[Si](Cl)(C)C.[CH2:33]1[O:36][CH:34]1[CH3:35]>CN(C=O)C.O>[OH:36][CH:34]([CH3:33])[CH2:35][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:33][CH:34]([OH:36])[CH3:35])[CH:18]=2)=[CH:4]1
Reactant: CC1CO1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Agent: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Cn1cc(C2=C(c3cn(CC(C)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
40 mg of a 60% suspension of sodium hydride in mineral oil was added to a solution of 327 mg of 3,4-bis-(3-indolyl)-1H-pyrrole-2,5-dione in 5 ml of DMF at 0° C. under nitrogen. After 0.5 hour the mixture was cooled to -20° C. and 108 mg of trimethylsilyl chloride were added. The mixture was allowed to warm to room temperature, then cooled to 0° C. and then a further 80 mg of sodium hydride were added thereto. After 0.5 hour at 0° C. 116 mg of propylene oxide were added and the mixture was stirred overnight. 5 ml of water were added and the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Recrystallization from diethyl ether/petroleum ether gave 30 mg of 3,4-bis[1-(2-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]=[O:15]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C(C)=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][C:14]([NH:13][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CCOC(=O)CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1cccc2ccc(C)nc12

Procedure:
A mixture of 15.9 g of 2-methyl-8-hydroxyquinoline, 13.6 g of ethyl isocyanatoacetate and 10 drops of dibutyltin dilaurate in 200 ml of methyl ethyl ketone was heated at reflux temperature for seven hours, after which the solvent was removed by evaporation in vacuo leaving a solid residue. The residue was recrystallized from toluene to give the desired ethyl N-(((2-methyl-8-quinolinyl)oxy)carbonyl)glycinate as light tan crystals, m.p. 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
To a dichloromethane solution (4 ml) of 4-chloropicolinic acid chloride (175 mg, 0.994 mmol), N-ethyldiisopropylamine (346 μl, 1.99 mol) and N-Boc-piperazine (278 mg, 1.49 mmol) were added, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1), to obtain 4-(4-chloro-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (166 mg, 51%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCCC)c1
Yield: 77 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 14 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-pentyloxybiphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 260 mg of 3-[3′-(3-heptyl-1-methylureido)-2-pentyloxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=69° C.). Yield=77% over the two steps.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[OH:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].CN.OC(O)CNC>C(N(CC)CC)C.ClCCl>[CH3:9][N:8]1[CH2:10][CH2:11][O:12][SiH:4]([CH3:2])[O:5][CH2:6][CH2:7]1
Reactant: CN(CCO)CCO
Reactant: [SiH3]C(Cl)Cl
Agent: CN
Agent: CNCC(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCO[SiH](C)OCC1
Yield: 73.5 %

Procedure:
To a sealed 800 mL nitrogen purged glass bottle was added 400 mL anhydrous dichloromethane and 98.2 mL triethylamine. Then, 3.65 mL (35 mmol) of 99+% dichloromethylsilane and 4.02 mL (35 mmol) di(hydroxyethyl)methylamine was added with shaking. This was repeated five times over twenty minutes until a total of 175 mmol of both dichloromethylsilane and di(hydroxyethyl)methylamine had been added. The bottle was agitated in a room temperature bath for 15 minutes. Then, five more additions of 4.02 mL (35 mmol) 99+% dichloromethylsilane and 4.02 mL (35 mmol) dihydroxyethyl)methylamine were done until a total of 36.44 mL (0.35 mol) of 99+% dichloromethylsilane and 40.2 mL (0.35 mol) dihydroxyethylmethylamine were reached. The bottle was then agitated overnight in a room temperature bath. The resulting solution was filtered and dichloromethane removed by rotary evaporation. To the residue was added 400 mL of pentane and solution was filtered again. Pentane was removed by rotary evaporation and product was isolated by vacuum distillation at 78-81° C. and 20 mm Hg (41.7 g, 73.5% yield). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.79 (1H, q), 3.83-3.71 (4H, m), 2.78-2.61 (4H, m), 2.37 (3H, s), 0.03 (3H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH2:36]>CCCCCCC.CC(=O)OCC>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH:36][C:25]([C:20]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: NCCc1ccccn1
Reactant: O=C(NCc1ccccc1-c1ccccc1C(=O)O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)OCc1ccccc1

Procedure:
From 0.28 mmol of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor 6) and 2-(2-pyridyl)ethylamine, according to ,the general working procedure and subsequent purification by flash chromatography 85 mg of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 140° C. (heptane/EA); MS (ES+): m/e=466 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: Cc1cc(=O)oc2cc(OCCBr)ccc12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCOc1ccc2c(C)cc(=O)oc2c1)OCC
Reaction time: 1 h

Procedure:
28.32 g. (0.1 mole) 7-(2'-bromo-ethyl-oxy)-4-methyl-coumarin and 33.23 g. (0.2 mole) triethylphosphite are heated under stirring for 1 hour. The reaction mixture is then cooled. The end-product is separated from the contaminations by removing same by vacuum distillation. The bottom product is a yellow, thick, oily substance of weight 11.9 g. (0.0035 mole), nD31 =1.5619.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC[O-].[Na+]>>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[O:24])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH3:23]
Reactant: CCOC(=O)CCCCc1ccc(OC)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(CCCc1ccc(OC)cc1)C(=O)OCC
Yield: 82.2 %

Procedure:
17.2 g of 3-ethoxycarbonyl-6-(4-methoxyphenyl)-2-oxocaproic acid ethyl ester are prepared from 14.7 g of 5-(4-methoxyphenyl)-valeric acid ethyl ester and 11.8 g of diethyl oxalate, using sodium ethylate as the base, in a manner analogous to that in Example (1b).
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]>C(Cl)Cl>[Br:1][CH:6]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[CH2:5][CH2:4][Cl:3]
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Temperature: 10 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of 358 g of bromine in 350 ml of methylene chloride is added dropwise to a solution of 483 g (2.23 mols) of 4-chlorophenyl 3-chloropropyl ketone in 1200 ml of methylene chloride at 20° C. Stirring is continued for one hour and the mixture is then evaporated down in vacuo. 300 ml of petroleum ether are added to the residue, and stirring is continued until crystallization is complete. The mixture is cooled to 10° C., and the precipitate is filtered off under suction. 582 g (88.3% of theory) of 4-chlorophenyl 1-bromo-3-chloropropyl ketone of melting point 73° C. are obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Nc1cccc(I)c1)C(F)(F)F
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NC(=O)C(F)(F)F)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.5 g. 1.6 mmol) and 1-iodo-3-trifluoroacetamidobenzene (0.5 g, 1.6 mmol) in triethylamine (10 mL) under an argon atmosphere was added a small amount of tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to give the title compound as a pale yellow solid (0.62 g, 78%), m.p. 63-65° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][OH:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].N12CCCN=C1CCCCC2>CN(C=O)C>[I:21][C:4]1[CH:5]=[C:6]2[C:11]3=[C:2]([O:14][CH2:13][CH2:12][N:10]3[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20])[CH:3]=1
Reactant: CCOC(=O)c1cn(CCO)c2c(F)cc(I)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A solution of ethyl 8-fluoro-1-(2-hydroxyethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 12, 20 mmol) in DMF (30 mL) was treated with 1.8-diazabicyclo[5.4.0]undec-7-ene (5.6 ml, 40 mmol) and the reaction mixture was stirred at 100° C. for 24 h. The solvent was then removed in vacuo and the residue was chromatographed on silica gel using 0-5% (0.2N ammonia in methanol) in dichloromethane to give 1.4 g (18%) of ethyl 9-iodo-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate as a white solid.
Reaction SMILES: Br[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1COCC1>[F:13][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]=1[NH2:6]
Reactant: CN1CCNCC1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(F)c(N)cc2C(F)(F)F)CC1
Temperature: 120 °C

Procedure:
To a microwave reaction tube was added 4-bromo-2-fluoro-5-(trifluoromethyl)aniline (256 mg, 1.0 mmol), 1-methylpiperazine (300 mg, 3 mmol) Pd2(dba)3 (91.5 mg, 0.1 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg, 0.2 mmol), NaOtBu (144 mg, 1.5 mmol) and THF (3 mL). After the reaction tube was degassed and filled with N2, the tube was heated to 120° C. in a microwave reactor for 40 min. The mixture was then poured into saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient MeOH/CH2Cl2, 0˜10%) to provide 2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline as a white solid. ESMS m/z 278.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)[OH:4].FC(F)[C:21](C(F)(F)F)([C:23]1C=C2C(=[CH:30][CH:31]=1)N(C(=O)CC(=O)C)CC2)[OH:22]>S(=O)(=O)(O)O>[F:18][CH:2]([F:1])[C:3]([C:5]1[CH:13]=[C:12]2[C:11]3=[C:7]([CH2:8][CH2:9][N:10]3[C:21](=[O:22])[CH:23]=[C:31]2[CH3:30])[CH:6]=1)([OH:4])[C:14]([F:17])([F:15])[F:16]
Reactant: OC(c1ccc2c(c1)CCN2)(C(F)F)C(F)(F)F
Reactant: CC(=O)CC(=O)N1CCc2cc(C(O)(C(F)F)C(F)(F)F)ccc21
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)F)C(F)(F)F)cc13)CC2

Procedure:
By the method of Example 7, α-(difluoromethyl)-α-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol is converted to α-(difluoromethyl)-α-(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 140°-143°, which is cyclized by heating in sulfuric acid to give 1,2-dihydro-8-[2,2,-difluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 317°-318°.