Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:45])[CH3:44])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2]>C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:38]=[CH:39][C:40]([CH:43]([OH:45])[CH3:44])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(C(C)=O)cc4)cc3)CC2)nc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cc4)cc3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Ethyl({[2-{[1-(4′-acetylbiphenyl-4-yl)piperidin-4-yl]methyl}-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.67 g, 1.1 mmol) was dissolved in a mixed solvent of ethyl acetate (35 mL) and dichloromethane (35 mL), and 10% palladium-activated carbon (0.65 g) was added, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere. After the reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.27 (dichloromethane/ethyl acetate=1/3) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.44 g, 0.82 mmol) as a white solid (yield 77%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1>CO>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C@:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)(F)F)cc2)(c2cccc(-c3cccnc3F)c2)N=C1N
Solvent: CO
Product: CN1C(=O)[C@@](c2ccc(OC(F)(F)F)cc2)(c2cccc(-c3cccnc3F)c2)N=C1N

Procedure:
A racemic mixture of 2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one was separated by chiral HPLC using Chiralcel AD, 2×25 cm (column) with mobile phase 9% EtOH in hexanes (0.1% diethylamine) to give the title R-isomer: [α]25=−13.4 (1% in MeOH); 1H NMR (DMSOd6 300 MHz) δ 2.95 (s, 3H), 6.65 (brs, 2H), 7.28 (d, 2H), 7.4-7.45 (m, 3H), 7.5 (m, 1H), 7.55 (d, 2H), 7.65 (d, 1H), 7.95-8.0 (m, 1H), 8.2 (m, 1H); MS m/e (M+H)+ 445.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.O.NN>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH2:5][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Agent: NN
Solvent: OCCO
Solvent: O
Product: Brc1cc(Br)cc(Cc2cccnc2)c1
Temperature: 80 °C

Procedure:
A solution of 3-(3,5-dibromobenzoyl)pyridine (Preparation 1; 19.0 g) and hydrazine hydrate (13.9 ml) in ethylene glycol (140 ml) was heated under reflux for 45 minutes. The volatile material was distilled off until the internal temperature reached 180° C, and then the reaction mixture was cooled to 80° C. Potassium hydroxide (7.80 g) was added and the resulting solution was heated under reflux for 30 minutes, cooled and then poured into water. The mixture was extracted several times with ethyl acetate, and the combined extracts were washed with water and dried (MgSO4). Evaporation under vacuum gave the title compound (16.38 g), m.p. 70°-72° C. (after crystallisation from ethyl acetate-hexane). Found: C, 44.29; H, 2.66; N, 4.29. C12H9 Br2N requires C, 44.07; H, 2.77; N, 4.28%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]([CH3:23])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>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.CCCCCC.CCOC(C)=O>[CH3:23][C@@H:11]1[CH2:10][N:9]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[CH:6]=[CH:7][C:2]([C:37]#[C:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(Br)cc2)CCN1CC(=O)OC(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 2-((R)-4-((S)-(4-bromophenyl)(phenyl)methyl)-2-methyl-piperazin-1-yl)acetate (459 mg, 0.1 mmol, its preparation follows the general procedures of Reference G), 1-phenylethyne (0.137 ml, 1.249 mmol), tetrabutylammonium fluoride trihydrate (946 mg, 2.997 mmol) and dichlorobis(triphenylphosphine)palladium(ii) (21.0 mg, 0.030 mmol) was heated at 80° C. under N2 atmosphere for 1 h. The residue was subjected to flash chromatography (SiO2, hexane to hexane/EtOAc=100:10 to 100:15 to 100:20) to give tert-butyl 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)methyl)-piperazin-1-yl)acetate (460 mg) as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:29][C:27]([N:17]([C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)[S:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:36]=[CH:35][C:34]([O:38][CH3:39])=[O:37])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:16])=[O:15])=[O:28])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1

Procedure:
A solution of 2-(4-iodophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.5 g), methyl acrylate (0.25 ml), palladium acetate (58 mg) and triethylamine (1.79 ml) in dimethyl formamide (45 ml) and water (5 ml) was heated at 100° C. for 1 hour. Volatile material was removed by evaporation and water (50 ml) was added to the residue. The mixture was acidfied to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (2×50 ml). The extracts were washed with water (50 ml) and saturated sodium chloride solution (50 ml), treated with charcoal and dried (MgSO4). The solvent was removed by evaporation and the residue was triturated with ether/hexane (1:1 v/v) to give N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.99 g), m.p. 149-151° C.; microanalysis found: C, 57.7; H, 5.2; N, 10.6%; C26H28N407S requires: C, 57.8; H, 5.2; N, 10.4%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77%). 1H NMR (400 MHz, d6-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28 (1H, s), 10.20 (1H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[N+:41]([O-:43])=[O:42]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[N+:41]([O-:43])=[O:42])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccc(C#N)cc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Yield: 94 %

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.353 g, 1.152 mmol) were added ACN (3.84 mL), DIEA (0.402 mL, 2.304 mmol) and 4-fluoro-3-nitrobenzonitrile (commercially available from J & W Pharmlab, Levittown, Pa.) (0.191 g, 1.152 mmol) respectively. After completion of reaction, the dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of product which was obtained as an orange/brown oil as a mixture of cis/trans isomers of (S)-4-((4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)cyclohexyl)amino)-3-nitrobenzonitrile (0.490 g, 1.083 mmol, 94% yield). m/z (ESI) 453.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.S(O)(O)(=O)=O.O[NH:77][C:78]([NH2:80])=[NH:79].ONC(N)=N>CN(C=O)C>[NH2:80][C:78]1[N:79]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:77]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: N=C(N)NO
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a solution of 11.9 g (30.7 mmol) of carboxylic acid from Example 4A in 150 ml of DMF was admixed at RT with 19.2 g (36.8 mmol) of PYBOP and 10.7 ml (61.4 mmol) of N,N′-diisopropylethylamine. Subsequently, the mixture was stirred at RT for 30 min and then the solution was added dropwise within 1.5 h to a suspension of 24.5 g (92.1 mmol) of hydroxyguanidine hemisulphate hemihydrate, 16.1 ml (92.1 mmol) of N,N′-diisopropylethylamine and 4 Å molecular sieve. The reaction mixture was stirred at RT for 1 h and then filtered through a frit. The residue was washed with 200 ml of DMF and then the combined organic phases were stirred at 130° C. (preheated oil bath) for 1.5 h. Subsequently, the solvent was removed under reduced pressure and the residue was admixed with 300 ml of diethyl ether and 300 ml of 1 N aqueous sodium hydroxide solution, and stirred vigorously for 24 h. The solid formed was filtered off, washed with water and diethyl ether and then dried under high vacuum. Yield: 8.80 g (66% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Cl)c(C)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(Cl)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 6-chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([CH3:6])[C:3](=[NH:5])[CH3:4].[C:12]1([CH3:29])[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:13]=1.CCCCCC>C(OCC)C.COCCOCCOC>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:2]([C:3]1[N:5]=[C:24]([OH:25])[C:18]([C:14]2[CH:13]=[C:12]([CH3:29])[CH:17]=[CH:16][CH:15]=2)=[C:19]([OH:20])[CH:4]=1)([CH3:1])[CH3:6]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(C)c1
Reactant: CC(=N)C(C)(C)c1cccs1
Solvent: COCCOCCOC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cccc(-c2c(O)cc(C(C)(C)c3cccs3)nc2O)c1
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 2a (0.83 g, 5.5 mmol) in anhydrous diethyl ether (5 mL) was added under argon 1.6M methyl lithium in diethyl ether (21 mL, 33.00 mmol) and the mixture was stirred for 3 hrs. at room temperature. After quenching with water, the mixture was extracted with diethyl ether. The extracts were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford a colorless oil (0.86, 95%). A solution of the intermediate product (3-methyl-3-(thiophen-2-yl)butan-2-imine; 0.73 g, 4.36 mmol) and diethyl 2-m-tolylmalonate (0.70 g, 4.36 mmol) in 1 mL diglyme was refluxed at 135° C. for 3 hours. The reaction mixture was cooled and poured into hexane to afford a yellow precipitate, which was collected and crystallized from ethyl acetate/hexane mixture. Off white powder, Yield: 52% MS: (ESI, Neg) 323.90 (M−1) 1HNMR (500 MHz, DMSO-d6): ∂(ppm) 10.69(s, 1H), 10.19(s, 1H), 7.46(d, 1H), 7.11-7.19(m, 3H), 6.99-7.05(m, 3H), 5.78(s, 1H), 2.28(s, 3H), 1.72(s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:19]([NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1cc(N)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cn1cc(NS(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a suspension of ethyl 2-(3-amino-1H-indol-1-yl)acetate hydrochloride (220 mg, 0.864 mmol) in dry DCM (4 ml), cooled at 0° C. under nitrogen, methanesulfonyl chloride (67.3 μl, 0.864 mmol) and dry pyridine (559 μl, 6.91 mmol) were added. After stirring at 0° C. for 4 hours, the mixture was partitioned between 5% aqueous citric acid and DCM; the organic phase was washed with water, dried over Na2SO4 and evaporated to give ethyl 2-(3-(methylsulfonamido)-1H-indol-1-yl)acetate (221 mg, 0.746 mmol, 86% yield). MS/ESI+ 319.0 [MNa]+. This product was used in the next step without any additional purification.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].[C:8]1([C:14]([C:31]([F:34])([F:33])[F:32])=[C:15]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:31]([F:32])([F:33])[F:34])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: CN(C)CCO
Agent: [Na]
Product: COc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN(C)C)cc2)cc1
Yield: 89.5 %

Procedure:
0.46 g (0.02 g.-atoms) of sodium are dissolved in 4.5 g (50 mmoles) of 2-dimethylamino-ethanol. 3.72 g (10 mmoles) of 2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-1-(4-methoxyphenyl)-propene are added to the solution, the mixture is heated at 150°-155° C. for one hour, and then processed as described in Example 19. 3.95 g (89.6%) of 1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)propene are obtained as a resinous substance; the product is a 9:1 mixture of the (Z) and (E) isomers.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:9][C:8]=1[C:14]([F:16])([F:15])[F:17]
Reactant: COC(C)(C)CCOc1ccc(N)cc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)CCOc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, 4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)aniline (490 mg, 1.77 mmoles) was dissolved in 20 mL of dry tetrahydrofuran. To this solution was added potassium carbonate (318 mg, 2.30 mmoles) followed by phenyl chloroformate (360 mg, 2.30 mmoles). The mixture was stirred overnight at room temperature, then purified with silica gel chromatography (using a gradient of 0-30% ethyl acetate/hexanes) to afford phenyl 4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)-phenylcarbamate as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58 (m, 2H), 7.40 (m, 2H), 7.35-7.1 (m, 4H), 6.9 (m, 1H), 4.10 (m, 2H), 3.22 (s, 3H), 2.1 (m, 2H), 2.1 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:17][CH3:18])=[O:8].[CH3:31][I:32]>>[I-:32].[F:30][C:2]([F:1])([F:29])[CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N+:12]1([CH2:17][CH3:18])[CH3:31])=[O:8]
Reactant: CCN1CCCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: CI
Product: CC[N+]1(C)CCCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: [I-]

Procedure:
Using the method of Example 37, 2,5-bis(2,2,2-trifluoroethoxy)-N-[(1-ethyl-2-piperidyl)methyl]benzamide is reacted with methyl iodide to provide 2-[2,5-bis(2,2,2-trifluoroethoxy)benzamidomethyl]-1-ethyl-1-methylpiperidinium iodide as a white solid, m.p. 162° -165° C.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:58])[CH2:47][CH2:48][N:49]([CH3:57])[C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1.N[C:60]1C=CC=C[CH:61]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:56][C:53]5[CH:54]=[CH:55][C:50]([N:49]([CH2:48][CH2:47][N:46]([CH3:58])[CH3:45])[CH3:57])=[CH:51][CH:52]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:60][CH2:61]1)[CH2:5][O:12][CH2:9]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(N(C)CCN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,4-diamine as the aniline component. (40%, MS=570.5 (M+H))
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Yield: 72.6 %

Procedure:
3.42 g of 4,5-dimethyl-1,3-dioxolen-2-one [compound of formula (III') in which R is methyl, prepared in accordance with the procedure described in Tetrahedron Letters, pages 1701-1704, (1972)] was dissolved in 150 ml of carbon tetrachloride. To the solution were added 5.34 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile. The mixture was heated under reflux for 15 minutes. The reaction mixture was cooled with ice, and the insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give a syrupy residue. The residue was distilled under reduced pressure, and a fraction having a boiling point of 115° to 120° C./5 mmHg was recovered. Thus, 4.2 g (yield 73%) of the captioned compound having the following properties was obtained as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.C1C(=O)N([Br:25])C(=O)C1>>[Br:25][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
1,3-Dinitrobenzene (25 g, 149 mmol) was dissolved in sulfuric acid (44.5 mL, 835 mmol) and NBS (31.8 g, 178 mmol) was added. The mixture was stirred at 60° C. for 2 days. The reaction was cooled to ambient temperature and the mixture was poured into ice water to form a precipitate. The product was collected by filtration, washed with water and hexanes to yield 35.1 g (142 mmol, 96%) of 1-bromo-3,5-dinitrobenzene as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[Br:18]Br>CC(O)=O>[Br:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: BrBr
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (200 mg, 0.85 mmol) in 0.5 ml of AcOH was added Br2 (0.07 ml, 1.28 mmol). The resulting dark-orange solution was stirred at room temperature for overnight. The excess bromine was removed under reduced pressure. Then the solution was poured into 5 ml of water and extracted with ethyl acetate (3×3 ml). The combined ethyl acetate layers were further washed with NaHCO3 (sat.), brine and dried over MgSO4. After concentration, the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/3) to yield the desired product (170 mg, as white solids.