Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][CH:35]=1.C1N2CCN(CC2)C1>>[CH3:39][O:38][C:36]([C:33]1[CH:32]=[N:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:35][N:34]=1)=[O:37]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cn1

Procedure:
In analogy to Example 62, step 1, 6-[(2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was react with methyl 5-chloro-2-pyrazine carboxylate and DABCO (1.5 h, r.t.) to give the title compound as a white solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:17]2[CH2:16][CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:23][CH:22]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Reactant: Fc1ccc(OCCBr)cc1
Product: Fc1ccc(OCCN2CC=C(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (8) synthesized in Example 1 and 2-(4-fluorophenyl)oxyethyl bromide to produce the above.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Yield: 49.3 %

Procedure:
8.10 g p-nitro-bromobenzene was added into a 250 ml round-bottom flask containing 50 mL isopropanol, then 7.00 g anhydrous piperazine, 15.00 g anhydrous K3PO4 and 4 ml glycol was added, then 2.00 g CuI was added as catalyster under nitrogen atmosphere (the small-scale reaction was carried out in the absence of nitrogen atmosphere, the results showed mat the yield was low probably because of the oxidation of CuI). The reaction mixture was refluxed for two days under nitrogen atmosphere. The crude product was filtered and concentrated. The concentrate was extracted with chloroform/water. The chloroform extract was dried by anhydrous Na2SO4. Based on higher polarity of product and lower polarity of the starting material, the extract was purified by column-chromatography with gradient elution of petroleum ether:ethyl acetate:ethanol in differ ratio, concentrated the eluate, to produce N-4-nitro-phenyl piperazine as yellow solid (4.10 g, 49.4% yield). Mp: 126-128° C. (lit.: 130-132° C.)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[O:14])=[C:11]([CH3:31])[N:10]=1>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:29]=[CH:30][C:9]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[N:10][C:11]=2[CH3:31])=[CH:17][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cccn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 52 mg of pyrazole and 18 mg of sodium hydride in 2 mL of DMF were stirred for 10 min. 90 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 5 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-pyrazol-1-yl)nicotinamide. MS (Q1) 390.0 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a stirred mixture of 2-bromo-4-fluorotrifluoromethylbenzene (33.7 g, 0.1387 mol) in sulfuric acid (98%, 34 mL) at 5° C. under nitrogen is added dropwise a mixture of sulfuric acid (98%, 10.1 mL) with fuming nitric acid (6.7 mL). The mixture is warmed up to room temperature for 2 hours and cooled down to 5° C. before adding water (60 mL). The resulting mixture is extracted twice with ethyl acetate (10 mL). The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate (60 mL), water (60 mL) and dried over sodium sulfate. Concentration affords the title compound as a yellow solid (37.1 g, 92.9%)
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([CH2:26][C:27]([N:1]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:28])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: C1COCCOCCOCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and (1-adamantyl)acetyl chloride.
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>ClCCl>[CH2:32]([O:31][C:29]([CH:28]1[CH:22]2[CH:23]1[CH2:24][CH2:25][CH:19]([O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:20][CH2:21]2)=[O:30])[CH3:33]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](OC1CCC=CCC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1C2CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCC21

Procedure:
To a solution of Example 8C (2.2 g, 6.28 mmoles) and Rh2(OAc)4 (2 mg, 4.3 μmol) in dichloromethane (2 mL), ethyl diazoacetate (0.717 g, 6.28 mmoles) in dichloromethane (4 mL) was added over two hours via a syringe pump. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 80:20) to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=1
Reactant: Clc1ccc(-c2cn3ccnc3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3ccnc23)nc1
Temperature: 120 °C

Procedure:
108 mg (0.3625 mmol) of the 8-chloro-6-(2,4-dichlorophenyl)imidazo[1,2-a]pyrazine (Example 5A) were initially charged in 3 ml of DMSO, and 150 mg (0.543 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile (Example 2A) and 0.63 ml (3.62 mmol) of N,N-diisopropylethylamine were added. The mixture was heated at 120° C. for 12 h. Purification by chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 100:1) gave 12 mg (7% of theory) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:8]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cn[nH]c1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1cnn(C(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of 4-bromo-1H-pyrazole (0.294 g), (bromomethylene)dibenzene (0.494 g) and triethylamine (0.418 mL) in tetrahydrofuran (5 mL) was stirred at 60° C. for 24 hours. The reaction mixture was concentrated and purified by chromatography on silica gel using 0-20% ethyl acetate/hexanes as eluent to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=2)=[O:15])[CH2:10]1)[S:3](=[O:8])(=[O:7])[N:4]([CH3:6])[CH3:5].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:17]=2)=[O:15])[CH2:10]1)[S:3](=[O:8])(=[O:7])[N:4]([CH3:6])[CH3:5]
Reactant: CN(C)S(=O)(=O)N(C)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)S(=O)(=O)N(C)C)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-dimethylsulfamic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 513 (MH+); HPLC Rf: 4.76 min.; HPLC purity 92%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.O>CN(C=O)C.[Cu](I)I>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(Cc2ccncc2)cc1
Reactant: OCC(F)(F)F
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(Cc2ccncc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
In a stream of nitrogen, 2.0 ml of 2,2,2-trifluoroethanol was added to 52.8 mg of sodium hydride, and then a solution of 140 mg of copper iodide and 922 mg of 4-(4-bromobenzyl)pyridine in 4 ml of N,N'-dimethylformamide was added. The mixture was stirred at a bath temperature of 120° C. for 3 hours. After the reaction, water was added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with water, and the solvent was evaporated. 0.78 g of the residue was distilled under reduced pressure by using a Kugel-Rohr. When 574 mg (yield 57%) of a fraction having a boiling point of 150° C. (0.2 mmHg) was separated, 4-[4-(2,2,2-trifluoroethoxy)benzyl]pyridine was obtained as colorless crystals having a melting point of 51° to 53° C.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1O)=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:1]=[O:2])[CH3:15]
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: CCN
Product: CCNc1ccc2ccccc2c1N=O

Procedure:
The starting 2-ethylamino-1-nitrosonaphthalene is prepared by reacting 1-nitroso-2-naphthol with ethylamine following the same procedure described in the second part of example 12.
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH3:13])[O:10][N:9]=1.CN(C)CCN(C)C.[C:22](=[O:24])=[O:23]>CCCCCC.O1CCCC1>[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH2:13][C:22]([OH:24])=[O:23])[O:10][N:9]=1
Reactant: Cc1nc(CO)no1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)Cc1nc(CO)no1
Temperature: 35 °C
Yield: 55 %

Procedure:
Under anhydrous conditions, a solution of approximately 1.2 mol of n-butyl lithium in n-hexane was added dropwise over 3 hours to an efficiently cooled solution of 66 g (0.58 mol) of 3-hydroxymethyl-5-methyl-1,2,4-oxadiazol and 87 ml of N,N,N',N'-tetramethyl ethylene diamine in 1200 ml of tetrahydrofuran and during the addition, the reaction temperature was not allowed to rise above -70° C. The reaction mixture was stirred for 1 hour at -70° C. and under efficient cooling, dried gaseous carbon dioxide was passed over the surface of the stirred reaction mixture for ten hours at -70° C. Subsequently, the temperature was allowed to rise gradually to -5° C. and the formed precipitate was collected by vacuum filtration and was washed with dry ethyl acetate and with n-hexane. The precipitate was dissolved slowly by adding it in small portions to a stirred icy-cold mixture of 500 ml of water and 500 ml of diethyl ether and concentrated phosphoric acid was added till the pH was 4.0. The layers were separated and the organic layer discarded. The water-layer was further acidified to a pH of 2.0 and subsequently evaporated in vacuo. Remnants of water in the residue were removed in vacuo with the help of benzene and the residue was dried in vacuo over phosphorous pentoxide for 16 hours. The syrupy product was stirred with 500 ml of acetone at about 35° C. and the acetone was decanted. This was repeated once whereupon the residue became a solid mass which was transferred to a filter and repeatedly stirred with 500 ml portions of acetone until according to thin-layer chromatograms the filtrate no longer contained the desired compound. All filtrates were combined (total of about 4000 ml) and concentrated in vacuo to a volume of about 300 ml. 600 ml of ethyl acetate were added and the resulting solution was again concentrated in vacuo to a final volume of about 250 ml. The resulting crystalline precipitate was vacuum filtered, washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g of 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid were obtained with melting and decomposition taking place between about 96° and 98° C. The filtrate was evaporated in vacuo and the oily residue was repeatedly stirred with small volumes of dichloromethane. The resulting solid was transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second crop of said product weighed 14.1 g and melted with extensive decomposition at 92°-96° C. According to thin-layer chromatograms, IR and PMR spectra both crops were virtually identical for a total of 45.1 g (about 55% yield) of about 96% purity.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16].C(N(C(C)C)C(C)C)C>C(O)C>[OH:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)CS1
Yield: 36 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (870 mg) in ethanol (30 mL) were added cis-2-aminocyclohexanol hydrochloride (1.00 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.32 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (504 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3](S(C2C=CC=CC=2)(=O)=O)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Yield: 138.7 %

Procedure:
A mixture of 2-methyl-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole (13.5 g, 39.82 mmol; step C above) and K2CO3 (27.5 g) in MeOH/H2O (2:1, 300 mL) was heated at reflux temperature. After 14 h the mixture was cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×2). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 1:1 EtOAc/hexanes eluent), affording 11.0 g of the deprotected indole as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 2.48 (s, 3H); MS (ES) m/z 200 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.Cl>[OH-].[Na+]>[CH3:12][CH:7]1[N:8]2[C:9]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH3:13])[C:4]=3[CH2:5][CH2:6]1)[C:17](=[O:16])[C:18]([C:19]([OH:21])=[O:20])=[CH:24]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(F)ccc2c1CCC(C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 9.3 g of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine and 17 ml of diethyl ethoxymethylenemalonate was heated at 150°-160° C. for 3.5 hours, and then cooled to 100° C. To this solution was added 56 g of polyphosphoric acid, and the mixture was stirred for one hour while heating on a steam bath. The mixture was then cooled to room temperature and allowed to stand for about 72 hours. To this mixture, containing ethyl 1,2-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, was added 250 ml of 20% aqueous sodium hydroxide to make the solution basic. The solution was then heated at its reflux temperature for 2 hours, cooled, and acidified with concentrated hydrochloric acid. The solid was separated by filtration and recrystallized from aqueous N,N-dimethylformamide. Washing with ethanol followed by drying provided 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as an off-white solid, m.p. 269°-272° C. Analysis: Calculated for C15H14FNO3 : %C, 65.4; %H, 5.1; %N, 5.1; Found: %C, 65.0; %H, 5.0; %N, 5.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([NH:28][C:29](=O)[O:30]C(C)=C)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:28][C:29]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:30])([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: C=C(C)OC(=O)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(OC)cn1
Solvent: C1CCOC1
Product: COc1ccc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2cc(F)cc(C(F)(F)F)c2)nc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 62.8 %

Procedure:
To a solution of prop-1-en-2-yl 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2-phenylethylcarbamate (100 mg, 0.210 mmol) in THF (200 μl) was added 2,2,2-trifluoroethanamine (200 μl, 2.1 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 1200 sec then at 150° C. for 1800 sec. The solvent was evaporated under reduced pressure and the residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-100% over 12 min) to give (R)-1-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2 phenylethyl)-3-(2,2,2-trifluoroethyl)urea as white powder (68 mg, 63% yield) LCMS: RT=2.03 min [M+H] 516.2 (LCMS Method 1); HPLC: RT=3.24 min, Purity 98% (HPLC Method 2); NMR: 400 MHz 1H (CD3OD) 8.30 ppm, 1H, s; 7.98 ppm, 1H, dd, J=4.55, 1.26 Hz; 7.46ppm, 1H, s; 7.39 ppm, 2H, m; 7.30 ppm, 1H, m; 7.21 ppm, 1H, m; 7.00 ppm, 3H, m; 6.66 ppm, 2H, m; 4.18 ppm, 2H, m; 3.90 ppm, 1H, m; 3.63 ppm, 4H, m.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NNc1ccc(N)cc1
Yield: 74.7 %

Procedure:
16.6 g of 1-acetyl-2-(4-nitrophenyl)hydrazine was catalytically reduced at room temperature in 800 ml of ethanol using a palladium-carbon catalyst. The reaction solution was filtered and cooled to obtain 10.5 g of 1-acetyl-2-(4-aminophenyl)hydrazine. Yield: 75%. Melting point: 130°-140° C.
Reaction SMILES: [F:1][C@:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].Cl.[CH3:22][NH:23][OH:24]>>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@:2]([F:1])([CH3:6])[C:3]([N:23]([OH:24])[CH3:22])=[O:4])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: CNO
Reactant: C[C@@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Product: CN(O)C(=O)[C@@](C)(F)c1ccc(OS(=O)(=O)C(F)(F)F)cc1

Procedure:
Following the same procedure described for 4 and starting from 2 (1.6 mmol) and N-methylhydroxylamine hydrochloride (2 mmol), after workup compound 5 was isolated as a colourless oil (0.34 g, yield 63%). [α]D=+10.5 (c=0.5; CH3OH). 1H-NMR (CDCl3) δ 7.65 (d, 2H, J=7 Hz), 7.30 (d, 2H, J=7 Hz), 2.90 (s, 3H), 1.94 (d, 3H, J=23 Hz).