Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([NH2:41])=[O:40]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:38][C:39]([NH2:41])=[O:40])=[CH:26][C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3]1
Reactant: NC(=O)CBr
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 165 °C
Yield: 95.6 %

Procedure:
The product of Example 320C (0.125 g, 0.29 mmol) was reacted with cesium carbonate (0.38 g, 1.17 mmol), 2-bromoacetamide (0.060 g, 0.43 mmol) and a catalytic amount of tetrabuylammonium iodide in N,N-dimethylformamide (3 mL) at 25° C. for 2 hours. The reaction was concentrated to half the volume under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.134 g, 95%). MS (ESI−) m/z 482 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.21 (m, J=3.86, 2.39 Hz, 2 H) 0.46 (m, 2 H) 0.99 (m, 1 H) 2.55 (m, 2 H) 4.49 (s, 2 H) 5.96 (t, J=6.43 Hz, 1 H) 7.06 (m, 1 H) 7.21 (m, 2 H) 7.40 (m, 2 H) 7.53 (m, 1 H) 7.62 (m, J=1.84 Hz, 1 H) 7.67 (d, J=8.46 Hz, 1 H) 8.07 (dd, J=8.09, 1.47 Hz, 1H) 16.25 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C[NH:26][C@@H]1CCCC[C@H]1NC.[N-]=[N+]=[N-].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.O.CC(OC)(C)C.[Cu]I>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[C:20]([NH2:26])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cc(Br)ccc2F)COC1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [N-]=[N+]=[N-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(CF)(c2cc(N)ccc2F)COC1
Temperature: 70 °C

Procedure:
To a solution of 0.69 g (1.703 mmol) [5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester and 72.7 mg (0.511 mmol) trans-N,N′-dimethylcyclohexane-1,2-diamine in 7.5 ml EtOH was added a solution of 443 mg (6.81 mmol) sodium azide and 67.5 g (0.341 mmol) sodium-ascorbate in 3 ml water. The mixture was degassed and brought under nitrogen atmosphere. CuI (64.9 mg, 0.341 mmol) was added and the mixture was heated at 70° C. The initially formed suspension turned into a homogeneous blue solution. The mixture was cooled to rt, diluted with water and TBME. The organic phase was washed with brine and dried with MgSO4.H2O. The crude product, consisting of a mixture of aryl azide and aniline, was dissolved in 3 ml EtOH and 3 ml THF and treated with 20 mg 10% Pd—C and stirred under an atmosphere of hydrogen until all azide had been consumed. The mixture was diluted with DCM and filtered over celite. The product was purified by chromatography on silica gel (heptane/30% EtOAc) to give the desired product as colorless foam.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.[OH-].[Na+]>>[C:2]([C:1]1[O:6][CH:11]=[C:10]([CH2:9][Cl:8])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nc(CCl)co1
Temperature: 135 °C
Yield: 51.2 %

Procedure:
25 g of pivalic acid amide and 25 g of 1,3-dichloro-2-propanone were mixed and heated on an oil bath at 135° C. for 2.5 hours. After having been cooled with ice, the mixture was made alkaline with an aqueous solution of sodium hydroxide added thereto. Then, the resulting product was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through column chromatography (silica gel; ethyl acetate:n-hexane=1:8) to obtain 17.5 g of 2-tert-butyl-4-chloromethyloxazole.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[CH3:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16])=[CH:8][C:9]=2[CH3:15])[CH3:14])=[CH:23][C:22]=1[CH3:29]
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
A mixture of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine (643 mg, 2.6 mmol, 1.2 eq) and 4-formyl-2-methyl-benzoic acid methyl ester (380 mg, 2.1 mmol), acetic acid (252 mg, 4.2 mmol, 2.0 eq.), sodium triacetoxyborohydride (890 mg, 4.2 mmol, 2.0 eq.) in 1,2-dichloroethane is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the resulting residue is partitioned between EtOAc (50 mL) and 5% NaHCO3 (40 mL). The organic. phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography eluting with a gradient of EtOAc/Hexane to afford the title compound as a syrup (1.0 g, 95%). LC-ES/MS m/e 414.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:18]3[NH:17][C:16]4[CH:19]5[CH2:25][CH2:24][N:22]([CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]5)=[CH:4][CH:3]=1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[C:18]3[NH:17][C:16]4[CH:19]5[CH2:25][CH2:24][N:22]([CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]5)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#Cc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Cc1ccc(/C=C\c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Example 3 (100.9 mg, 0.308 mmol) was dissolved in methanol (5 mL). Lindlar catalyst (5% Pd on CaCO3 poisoned with lead, Aldrich, 9.8 mg) was added to the reaction mixture. The reaction flask was purged with nitrogen then purged with hydrogen, and the mixture was stirred under hydrogen (1 atm) at room temperature for 3 hours. The flask was purged with nitrogen and the reaction mixture was filtered. The filtrate was concentrated under vacuum, and the residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.01-2.10 (m, 4H), 2.41 (s, 3H), 2.97-3.13 (m, 3H), 3.21-3.26 (m, 2H), 26 (s, 2H), 6.69 (d, J=12.2 Hz, 1H), 6.88-6.90 (m, 2H), 6.99 (d, J=11.9 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.21-7.26 (m, 1H) 7.44 (dd, J=8.2, 2.0 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H); MS (APCI) m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a dichloromethane solution (1000 ml) of (2R)-2-(benzyloxy)propionic acid (51.7 g) and tert-butyl 4-aminopiperidine-1-carboxylate (63.2 g) were added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60.5 g) and 1-hydroxybenzotriazole monohydrate (42.7 g), followed by stirring overnight. The reaction solution was poured into a 0.5 N aqueous hydrochloric acid solution, and extracted with dichloromethane. The organic layer was washed sequentially with water, a saturated aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-{[(2R)-2-(benzyloxy)propanoyl]amino}piperidine-1-carboxylate (100 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[S:5][CH:6]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[S:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:12]
Reactant: O=C(c1cc(Br)cs1)C(F)(F)F
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: O=C(O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1
Yield: 46 %

Procedure:
This compound was synthesized from 1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (400 mg, yield 46%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.19 (br s, 1H), 8.85 (d, J=1.2 Hz, 1H), 8.50 (s, 1H), 8.29 (m, 1H), 8.10-8.08 (d, J=7.6 Hz, 1H), 7.96-7.94 (d, J=7.6 Hz, 1H), 7.62-7.59 (t, J=7.8 Hz, 1H). MS (ESI) m/z: Calculated for C13H7F3O3S: 300.01. found: 298.9 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[C:33]1([CH2:39]C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=CCc1ccccc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (1.21 g, 3.49 mmol) in 5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (5.0 mL) and phenylacetaldehyde (5.3 mL, 2M/in DMF, 5.3 mmol) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 1.18 g, 5.3 mmol.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×60 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (30 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography to give 6. IR (film, cm−1) 3060, 3026, 2934, 2854, 2800, 2765, 1662, 1495, 1452, 1401, 1262, 1203, 1150, 1106, 966, 1033, 775, 749; LRMS 351.
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH:12](=[C:10]([NH2:11])[C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)C2CCC1(CN)CC2
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC1(C(N)=Cc1ccccc1)CC2

Procedure:
10-Bornanamine (824mg) in toluene (20ml) was treated with benzaldehyde (0.55ml) and the solution refluxed under nitrogen under a Dean and Stark water trap for four days. Evaporation of the solvent in vacuo afforded impure 10-benzylidene-10-bornanamine which was dissolved in dimethoxyethane (10ml) containing lithium aluminium hydride (112mg.). The resulting mixture was refluxed for 2.25 hours, cooled, and the excess hydride decomposed by the addition of water. The precipitated inorganic material was removed by filtration and the solvent was evaporated in vacuo. The residual gum was triturated with 2N-hydrochloric acid to afford an insoluble hydrochloride which was collected by filtration and then partitioned between ether and 2N-sodium hydroxide. The dried ethereal layer was evaporated in vacuo to give a yellow oil which was dissolved in ether and treated with ethanolic hydrogen chloride. The precipitated solid was collected and recrystallized from water to give title compound m.p. 310° (Found: C, 72.65; H, 9.65; Cl, 13.3; N, 4.95. C17H26ClN requires C, 72.95; H, 9.35; Cl, 12.65; N, 5.0%).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]1[C:60]2=[C:61]([C:65](O)=[O:66])[N:62]=[CH:63][CH:64]=[C:59]2[CH:58]=[CH:57]1>CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)[C:65]([C:61]2[N:62]=[CH:63][CH:64]=[C:59]3[CH:58]=[CH:57][NH:56][C:60]=23)=[O:66])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Reactant: O=C(O)c1nccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2nccc3cc[nH]c23)cc1
Yield: 83.8 %

Procedure:
(4-tert-Butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine (90 mg, 0.27 mmol), N-methylmorpholine (74 mg, 0.73 mmol), and HBTU (139 mg, 0.37 mmol) were added at RT to a solution of 1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (66 mg) in DMF (3 mL), then after 64 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-dichloromethane gradient) afforded the title compound (108 mg, 86% over 2 steps). Light yellow oil, MS (ISP) 478.4 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([C:33](O)=[O:34])=[N:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Na+].[Cl-]>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:16]=[C:15]3[C:33](=[O:34])[NH:10][CH2:11][CH2:12][NH:13][C:14]=23)=[CH:20][CH:21]=1
Reactant: NCCNc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NCCNc2c1nn(-c1ccccc1Cl)c2-c1ccc(Cl)cc1
Reaction time: 17 h
Yield: 41.5 %

Procedure:
Diisopropylethylamine (209 microliters, 1.2 mmol) was added slowly via syringe to a solution of 4-(2-aminoethylamino)-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (I-4d, 228 mg, 0.53 mmol) and HATU (456 mg, 1.2 mmol) in anhydrous DMF (30 ml) at room temperature. The reaction mixture was stirred for 17 hours, diluted with saturated aqueous NaCl, and extracted with EtOAc (2×). The combined EtOAc extracts were washed with 0.5 M citric acid, 1 M K2CO3, and saturated aqueous NaCl, dried and concentrated in vacuo. The residue was slurried with CH2Cl2 and the organic solvent decanted, a process that was repeated twice. The combined organic solutions were concentrated in vacuo and the residue was purified on a chromatotron using 4 mm plates and a solvent gradient of 100% EtOAc to 10:1 EtOAC/MeOH to give I-4e as a colorless solid (82 mg): +ES MS (M+1) 373.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br-:10].[Br-:11].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:10][C:6]1[CH:5]=[C:4]2[C:9](=[C:8]([Br:11])[CH:7]=1)[NH:1][CH2:2][CH2:3]2
Reactant: [Br-]
Reactant: c1ccc2c(c1)CCN2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cc(Br)c2c(c1)CCN2
Yield: 84.1 %

Procedure:
Part A: Indoline (2.2 g, 18.04 mmol), dissolved in dichloromethane (160 mL) was stirred with pyridinium tribromide (12 g, 37.6 mmol) for 16 h at 25° C. The reaction was quenched with sat NaHSO3 (50 mL) and water (50 mL). The dichloromethane was separated, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 5,7-dibromoindoline (4.2 g, 84% yield). 1H NMR(CDCl3) δ 7.28 (m, 1H), 7.11 (s, 1H), 3.96 (s br, 1H ), 3.63 (t J=9 Hz, 1H), 3.13 (t J=9 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cccc(O)c1

Procedure:
1 g of 3-hydroxy-benzenepropanoic acid is mixed in 20 ml of methanol and 8 drops of sulphuric acid, the reaction medium is taken to reflux for 2 hours then evaporated under reduced pressure and purified by chromatography eluting with an AcOEt/Cyclohexane mixture 50/50. 1.07 g of expected product is obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[CH3:29].N>CN(C)C=O>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5](=[O:26])[C:6]2=[C:16]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:27])[CH3:29])=[CH:36][CH:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=C(Nc1ccc(CN(C)C)cc1)c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.57 mmol) 1,5-diacetyl-3-[ethoxy-phenyl-methylidene]-2-indolinone (Ex. III) are suspended in 5 ml of dimethylformamide and stirred with 86 mg 0.57 mmol) 4-dimethylaminomethyl-phenylamine at an ambient temperature of 80° C. for about 5 h. The acetyl-protected intermediate product is combined with 2 ml of conc. ammonia without being purified and stirred overnight at ambient temperature. Then the mixture is evaporated down and the residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[CH2:25][CH2:26][CH2:27]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2ccc3c(c2)CCC3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 67.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with indan-5-ol (35 mg, 0.26 mmol) to give the title compound (42 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].CS[C:19]([N:33]([CH3:42])[N:34]=CC1C=CC=CC=1)=[N:20][C:21](=O)[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:42][N:33]1[C:19]([NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[CH:2]=[O:3])=[N:20][C:21]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:34]1
Reactant: CSC(=NC(=O)CS(=O)(=O)c1ccccc1)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(CS(=O)(=O)c2ccccc2)nc1NCCCOc1cccc(C=O)c1
Yield: 70.5 %

Procedure:
A mixture of 3-[3-(1,3-dioxolan-2-yl)phenoxy]propanamine (2.3 g) and methyl-1-methyl-2-(phenylmethylene)-N-[2-(phenylsulphonyl)acetyl]hydrazine carboximidothioate (4.0 g) was heated at 60° under water pump vacuum for 3 h. The reaction mixture was dissolved in toluene (100 ml), 5N hydrochloric acid (100 ml) and acetone (50 ml) and stirred at room temperature for 18 h. The aqueous layer was basified to pH 9 with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to give the title compound as an amber gum (3.0 g) T.l.c. Methanol; Rf 0.8.
Reaction SMILES: F[B-](F)(F)F.Cl[C:7]1[CH:12]=CC=C(Cl)[N+]=1CC.C(O)C.[C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:19]1([CH2:25][C:26]([O:28][CH2:7][CH3:12])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CC[n+]1c(Cl)cccc1Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)Cc1ccccc1
Yield: 90 %

Procedure:
To a CH2Cl2 (2 ml) solution of 2,6-dichloro-1-ethylpyridinium tetrafluoroborate (630 mg, 2.4 mmol) was added a mixture of ethyl alcohol (92 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and ethyl phenylacetate was isolated in 90% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH2:15])(=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>CO>[NH2:24][C:23]1[C:20]([C:21]#[N:22])=[C:19]([C:18]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=2[Cl:16])[N:15]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]=1
Reactant: N=C(N)c1ccccc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (4.34 g, 31.4 mmol) and benzamidine (2.59 g, 21.5 mmol) were added at to a suspension of 2-(2,4-dichloro-benzylidene)-malononitrile (4 g, 17.9 mmol) in methanol. The yellow mixture was stirred for 1 h at room temperature and then heated to reflux for an additional 2 h. After cooling, the solvent was removed at reduced pressure, the residue was taken up in ethyl acetate/ice. The organic phase was separated, washed with water, and dried over sodium sulfate. The solvent was evaporated, the orange residue was taken up in acetone, and 1.91 g potassium manganate was added. After stirring for 90 min, the reaction mixture was filtered through decalite and evaporated. Purification by flash chromatography (silica gel, EtOAc/hexanes) afforded the title compound, MS: m/e=340.8 (M+), as a solid (2.63 g, 43%).