Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+]>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:12]([CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:13]
Reactant: ClCc1cccc2nnsc12
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCc1cccc2nnsc12
Reaction time: 8 h

Procedure:
18.4 g of 7-chloromethylbenzo-1,2,3-thiadiazole are dissolved in 50 ml of chloroform, 0.5 g of tetrabutylammonium iodide are added, the mixture is heated to 50°-55° C. and treated dropwise in the course of 0.5 hours with a solution of 5.6 g of sodium cyanide in 20 ml of water, with stirring. Heating is continued overnight at the same temperature, on the following day the mixture is cooled, treated with water and extracted several times using dichloromethane. The extracts are washed with water, dried over sodium sulfate and filtered over Hyflo, and the filtrate is evaporated. The residue is purified on silica gel (hexane/ethyl acetate) resulting in the title compound of m.p. 78°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 21 h
Yield: 97 %

Procedure:
A dry 5 1, 3-neck flask with mechanical stirrer, connected to a mineral oil bubbler, was charged with m-bromophenol (A) (150 g, 870 mmol), dry tetrahydrofuran (THF, 2 l) and triethylamine (132.1 g, 1.3 mol). The contents of the flask were cooled to 0° C., and chlorotrimethylsilane was added dropwise. A voluminous white precipitate was formed. The reaction was allowed to equilibrate to room temperature over a period of 21 h. The mixture was then filtered to remove triethylamine hydrochloride. Removal of solvents precipitated some remaining hydrochloride salt. The mixture was further purified by repeatedly adding hexane followed by filtration to yield 3-bromo-O-trimethylsilylphenol (B) (207 g, 97% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15](F)(F)F)=[CH:7][CH:6]=1)=[O:4].[F:21][C:22]([F:36])([F:35])[CH2:23]CCOC1C=CC(C=O)=CC=1.FC(F)(F)CCCCCOC1C=CC(C=O)=CC=1>>[F:1][C:2]([F:20])([F:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:23][C:22]([F:36])([F:35])[F:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Reactant: O=Cc1ccc(OCCCC(F)(F)F)cc1
Agent: O=Cc1ccc(OCCCCCC(F)(F)F)cc1
Product: O=C(c1ccc(OCCCCCC(F)(F)F)cc1)C(F)(F)F

Procedure:
Intermediate 8B was prepared using a procedure analogous to Intermediate 2C except that Intermediate 2A was replaced with Intermediate 8A. 1H NMR (500 MHz, CDCl3) δ 8.06-8.02 (m, 2H), 6.99-6.97 (m, 1H), 4.08 (t, J=6.2 Hz, 2H), 2.19-2.06 (m, 2H), 1.92-1.82 (m, 2H), 1.71-1.55 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([F:39])[CH:32]=1>ClCCl.CN(C=O)C>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([F:1])=[CH:3][C:4]=2[O:12][CH3:13])=[C:33]([F:39])[CH:32]=1
Reactant: COc1cc(F)c(C)cc1C(=O)O
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
Under a dry atmosphere of nitrogen, a solution of 4-fluoro-2-methoxy-5-methyl-benzoic acid (1.19 g, 6.47 mmol) in dichloromethane (16 mL, 0.5 M) was treated with oxalyl chloride (1.7 mL, 19.4 mmol) and a drop of DMF at 0° C. The mixture was allowed to gradually warm to room temperature and was then concentrated to afford a yellow powder. The powder was dissolved in dichloromethane (16 mL, 0.5 M). To the stirring solution at 0° C. was added diisopropylethylamine (2.8 mL, 16.2 mmol) followed by 4-bromo-2-fluorobenzylamine hydrochloride salt (2.34 g, 9.71 mmol). Stirring under nitrogen, the mixture was gradually allowed to warm to room temperature. After 21 hours, the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.33 g, 97%) as a brown oil which was used without further purification: Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.17 (bd s, 1 H), 8.06 (d, J=9.3 Hz, 1 H), 7.33–7.22 (m, 3 H), 6.65 (d, J=11.1 Hz, 1 H), 4.63 (d, J=6.3 Hz, 2 H), 3.92 (s, 3 H), 2.23 (bd d, J=1.8 Hz, 3 H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:21]2[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:9]3[CH:8]=[C:7]([NH2:6])[C:12]([F:13])=[CH:11][N:10]=3)=[CH:19][C:20]=2[F:26])[CH2:35]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ncc1F
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To 110 mg of N,N-dimethylformamide were added 23 mg of 1-(4-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 20 minutes. After adding 500 mg of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 23 mg of the title compound as a colorless powder.
Reaction SMILES: CS[C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[C:12]=3[CH:27]=2)=[N:5][N:4]=1.[C:28](#N)C.ClC1C=CC=C(C(OO)=O)C=1.[S:42]([O-:46])([O-])(=[O:44])=S.[Na+].[Na+]>CN(C)C(=O)C>[CH3:28][S:42]([C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=4)[C:12]=3[CH:27]=2)=[N:5][N:4]=1)(=[O:46])=[O:44]
Reactant: O=S([O-])([O-])=S
Reactant: CC#N
Reactant: CSc1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reaction time: 72 h
Yield: 61 %

Procedure:
To a mixture of 6-[5-(methylthio)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole (898 mg, 2.29 mmol), acetonitrile (10 mL) and N,N-dimethylacetamide (20 mL) was added m-chloroperbenzoic acid (1.21 g, 5.03 mmol) at room temperature, and the resulting mixture was stirred for 3 days. m-Chloroperbenzoic acid (605 mg, 2.52 mmol) was added to this mixture, and the mixture was further stirred at room temperature for 1 day. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (590 mg, yield 61%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:12]([O:11][P:10]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: CCc1cc(CCl)on1
Product: CCOP(=O)(Cc1cc(CC)no1)OCC
Reaction time: 2 h
Yield: 71.5 %

Procedure:
15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethyl phosphite are slowly heated to 150° C. and left at this temperature for 21/2 hours. After the mixture has cooled, it is distilled under reduced pressure. 18.2 g of (3-ethylisoxazol-5-yl)-methanephosphonic acid diethyl ester of boiling point 120°-121° C./0.2 mm Hg are obtained. Yield: 71.2%. 1H-NMR spectrum (CDCl3, with TMS as internal standard): τ=3.85 (d, J=3 Hz, 1H), 4.17 (m, J=Hz, 4H), 6.60 (d, H=20 Hz, 2H), 7.35 (q, J=Hz, 2H), 8.50-8.93 (m, 9H)
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].P(=O)([O-])[O-].[H][H].[O-:18][CH2:19][CH3:20].[Na+]>CCOCC.CN(C)C=O>[CH3:1][C:2]([CH:6]=[CH:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[CH:3][C:4]([O:18][CH2:19][CH3:20])=[O:5]
Reactant: CC[O-]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)CC=O
Agent: O=[PH]([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of one g. of 3,7-dimethyloct-6-en-1-al 1.5 g. of phosphonate (II; R' is ethyl, R1 is methyl, R6 is ethoxy, R12 is hydrogen) and 50 ml. of dimethylformamide, under nitrogen, is slowly added sodium ethoxide (prepared from 200 mg. of sodium and 12 ml. of ethanol). The mixture is allowed to stand at room temperature for one hour and then is worked up with ether. The ethereal extracts are dried, concentrated and then chromatographed on silica plates eluting with hexane/ether to yield ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate which is predominantly trans at position C-2,3 and C-4,5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (62 mg, 53%)
Reaction SMILES: O[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@@H](CO)CN1C(=O)COc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](CI)CN1C(=O)COc2ccccc21
Yield: 20 %

Procedure:
Crude (R)-4-(3-hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM40-37) (1.040 g), triphenylphosphine (0.99 g, 3.77 mmol), imidazole (0.32 g, 4.71 mmol) and iodine (1.43 g, 5.65 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the crude title compound (108LM46-43) (0.312 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+:5].[Na+].[P:7](O)(O)([O-:9])=[O:8].[NH4+].[O-:13][P:14]([O:17][P:18]([O-:21])([O-:20])=[O:19])(=[O:16])[O-:15].[Na+].[Na+].[Na+].[Na+].[O-][P:27]([O:30][P:31]([O:34][P:35]([O-:38])([O-:37])=[O:36])([O-:33])=[O:32])([O-:29])=[O:28].[Na+].[Na+].[Na+].[Na+].[Na+]>>[O-:16][P:14]1([O:15][P:7]([O-:9])(=[O:8])[O:38][P:35]([O-:37])(=[O:36])[O:34][P:31]([O-:33])(=[O:32])[O:30][P:27]([O-:29])(=[O:28])[O:20][P:18]([O-:21])(=[O:19])[O:17]1)=[O:13].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=P([O-])(O)O
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1

Procedure:
A process as claimed in claim 1, in which a 1:1 by weight mixture of sodium carbonate and monoammonium phosphate is subjected to the microwave radiation until a mixture of tetra sodium pyrophosphate, sodium tripolyphosphate and sodium hexametaphosphate is obtained.
Reaction SMILES: Cl.Cl.[O:3]1[C@@H:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C@H:7]2[NH:6][CH2:5][CH2:4]1.Cl[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C>C(#N)C.O>[CH3:20][N:19]1[C:15]([N:11]2[CH2:12][CH2:13][C@@H:7]3[NH:6][CH2:5][CH2:4][O:3][C@H:8]3[CH2:9][CH2:10]2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[N:18]1
Reactant: C1C[C@H]2NCCO[C@@H]2CCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@@H]2NCCO[C@H]2CC1

Procedure:
In a microwave reaction vial, (4aR,9aR)-2,3,4,4a,5,6,7,8,9,9a-decahydro-[1,4]oxazino[2,3-d]azepine dihydrochloride (509 mg; 2.22 mmol) and 5-chloro-1-methyl-4-nitro-pyrazole (322 mg, 2.00 mmol) were dissolved in acetonitrile (16 mL). DIPEA (3.11 mL, 17.77 mmol) was added and the mixture was irradiated with microwave at 130° C. for 60 min. The reaction mixture was diluted with water, extracted with EA 3×. Combined organic layers were dried over Na2SO4 and concentrated to give trans-7-(2-methyl-4-nitro-pyrazol-3-yl)-3,4,4a,5,6,8,9,9a-octahydro-2H-[1,4]oxazino[2,3-d]azepine. To a solution of this compound in DCM (15 mL) was added di-tert-butyl-dicarbonate (727 mg, 3.33 mmol) and DIPEA (1.16 mL, 6.66 mmol). The mixture was stirred at room temperature for 18 h. The crude reaction mixture was concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to gave the racemic trans-tert-butyl-7-(2-methyl-4-nitro-pyrazol-3-yl)-2,3,4a,5,6,8,9,9a-octahydro-[1,4]oxazino[2,3-d]azepine-4-carboxylate, which was chirally separated on AD column with 20% methanol w/0.1% NH4OH. The first eluting peak of trans-tert-butyl-7-(2-methyl-4-nitro-pyrazol-3-yl)-2,3,4a,5,6,8,9,9a-octahydro-[1,4]oxazino[2,3-d]azepine-4-carboxylate off the SFC chiral separation was converted to 396 following the procedures of Example 354. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.55 (s, 1H), 7.54-7.43 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.24-3.13 (m, 4H), 3.13-2.95 (m, 3H), 2.65 (d, J=5.6 Hz, 2H), 2.60-2.52 (m, 1H), 1.82-1.68 (m, 3H), 1.64-1.53 (m, 2H). LCMS (ES+) m/z 490 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].N#N.[CH3:13][CH2:14][OH:15].[Li][CH:17](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:13][C@H:14]([OH:15])[CH3:17]
Reactant: [Li]C(C)CC
Reactant: CCO
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: FB(F)F
Agent: N#N
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1cc(F)cc(F)c1F
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A solution of 1-bromo-2,3,5-trifluorobenzene (4.22 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give (2R)-1-(2,3,5-trifluorophenyl)propan-2-ol (3.14 g, 83%) as pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.12-7.26 (m, 1H), 6.76-6.96 (m, 1H), 4.09 (m, 1H), 2.85-2.88 (m, 2H), 1.47 (d, J=5.46 Hz, 1H), 1.26 (d, J=6.03 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=CC=[CH:14][C:13]=1O.O.C([O:23][CH2:24][CH3:25])(=O)C>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:25][C:24]([O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccccc1Cl
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 10.5 g (75.0 mmole) of 1-fluoro-4-nitrobenzene in 100 ml of dimethylsulfoxide and 9.64 g (75 mmole) of chlorophenol in 100 ml of DMSO was heated to 70° C. and maintained at this temperature for 4 hours. After allowing to cool to room temperature, 250 ml of water and then 250 ml of ethyl acetate were added slowly. The layers were separated and the organic layer was washed with 5×b 250 ml of water and 100 ml of sodium chloride, orange solid. Flash chromatography (CH2Cl2 eluent) yielded 18.34 g (98.0%) of the desired product as a yellow-orange solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH:22][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccccn2)cc1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
(4-Pyridin-2-yl-phenyl)-acetic acid (0.2 gm, 0.9 mmole), 3-fluorobenzylamine (0.14 ml, 1.lmmole), PyBOP (0.57 gm, 1.1 mmole), and DIEA (0.36 ml, 2.2 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.13 gm, 45%); H1-NMR INOVA-500 (DMSO d6) δ 3.563 (s, 2H), 4.305 (d, J=6.0 Hz, 2H), 7.032-7.095 (m, 3H), 7.332-7.360 (m, 2H), 7.404 (d, J=8.0 Hz, 2H), 7.874 (t, J=7.0 Hz, 1H), 7.948 (d, J=8.0 Hz, 1H), 8.034 (d, J=8.0 Hz, 2H), 8.659 (d, J=4. Hz, 2H). MS (m/z) 321.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O.N1CCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 5-fluoro-1,3-dihydroindol-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (A1) (21.1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 mL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL). The solid was stirred in ethanol (350 ml) at reflux for 0.5 h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93%) as orange solid. LC-MS observed [M−H]+: 299.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](Cl)=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[CH3:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH2:24].C1C=CC=CC=1.C(OCC)(=O)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:24][C:23]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:22]=3[CH3:21])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: Cc1cccc(C)c1N
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CCCCO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cccc3C)nc(=O)n1CC2

Procedure:
A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (2.5 g), 2,6-dimethylaniline (5.0 ml) in butanol (20.0 ml) is heated under reflux for 10 hours. The solvent is evaporated under reduced pressure to give a gummy mass. Chromatography of the gummy mass over silica gel using benzene-ethyl acetate as the eluant gives the required product. The compound is crystallized from methanol, yield 2.0 g, m.p. 297°-299° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[C:3](/[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4]/[OH:5].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl.CN(C1C=CN=CC=1)C.O>[F:1][C:2]([F:17])([F:18])/[C:3](/[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4]/[O:5][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cccc(/C(=N\O)C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(/C(=N\OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.