Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>COCCOC>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Brc1cnc(I)nc1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol) tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint, OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CN([CH:24]=[O:25])C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Reaction time: 0.33 h

Procedure:
In a flame-dried 3-necked 100 ml r.b. flask fitted with internal thermometer was prepared LDA at -78° using diisopropyl anine (2.8 ml, 19.9 mmol) and 2.5 M n-BuLi (8.32 ml, 20.8 mmol) in dry THF (15 ml). After stirring for 20 min, 4-chloropyridine (2.26 g, 19.9 mmol) in THF (5 ml) was added via a syringe pump at 0.15 ml/min over about 30 min. The mixture was stirred for 1 h, then dry DMF (4.8 ml, 62 mmol) was added via a syringe pump so that the temperature remained at -78°. After complete addition, the mixture was stirred 30 min then allowed to warm to -40° and hydrolyzed with 5% NaHCO3. The mixture was extracted twice with t-butyl methyl ether and washed with 5% NaHCO3, brine, dried (MgSO4), and concentrated. Chromatography (flash silica gel. 1:1 t-butyl methyl ether/hexanes) afforded the title compound as a white solid. (1.55 g, 55%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[C:18]([Cl:1])[CH:19]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 50 °C
Yield: 80.6 %

Procedure:
N-Chlorosuccinimide (391 mg, 2.93 mmol) was added to a solution of (4-amino-phenyl)-acetic acid ethyl ester (500 mg, 2.79 mmol; [5438-70-0]) in acetonitrile (10 ml) under an argon atmosphere. The reaction mixture was heated to 50° C. for 1 h. The solvent was removed under reduced pressure and the residue taken up in iPrOAc/brine 1/1. The layers were separated and the aqueous layer was extracted with iPrOAc. The combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (481 mg, 2.25 mmol; 81%) as brown oil. MS: m/e=214.1 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC1CCc2ccccc2C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1CCc2ccccc2C1=O
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Chloroacetyl chloride (14 g, 124 mmol) was added to a solution of 2-amino-3,4-dihydro-2H-naphthalen-1-one hydrochloride (16 g, 81 mmol) and triethylamine (41 g, 405 mmol) in tetrahydrofuran (600 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (7.58 g, 31.9 mmol, 39%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C1CSCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), thiomorpholine (3.0 g, 30 mmol), and K2CO3 (2.0 g, 14 mmol) in DMF (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The crude product that precipitated was collected by filtration, dried in vacuo, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 20% ether in CHCl3) and recrystallized three times from methanol (MeOH) (0.49 g, 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([N:22]3[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[N:24]=[CH:23]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:40][C:41]([NH:44][S:45]([C:48]1[S:52][C:51](Br)=[CH:50][CH:49]=1)(=[O:47])=[O:46])([CH3:43])[CH3:42].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:41]([NH:44][S:45]([C:48]1[S:52][C:51]([C:25]2[N:24]=[CH:23][N:22]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=3)[CH:26]=2)=[CH:50][CH:49]=1)(=[O:46])=[O:47])([CH3:43])([CH3:40])[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)c(C)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred mixture of 4-(3-methyl-4-trifluoromethyl-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.7) (0.33 g, 0.5 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.16 g, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) in toluene (6 mL) was heated under reflux conditions for 15 h, heptane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a light yellow solid.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C>C(N(CC)CC)C>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Yield: 84.2 %

Procedure:
To a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities) is charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (79.2 g), tert-butyl methyl ether (MTBE, 333 mL), and triethylamine (TEA, 666 mL). The reaction mixture is warmed to 55°±5° C. and allowed to react at that temperature for not less than 24 hours. As the reaction progresses, a slurry is formed. The extent of the reaction can be followed by HPLC until most of the initial reactants are consumed. At that point, the reaction mixture is cooled to 20°±5° C. and charged with MTBE (400 mL) and water (400 mL). The diluted slurry is mixed for at least 10 minutes and then aqueous and organic phases are allowed to separate in a separatory funnel. The aqueous phase is discarded and then the organic phase is washed with water two additional times. Carbon (20 g) is then added to the resultant organic phase, mixed for at least 10 minutes and the carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed. The CELITE® diatomaceous earth bed is washed with 200 ml of MTBE, the organic phases are combined and then solvent exchanged with ethanol under vacuum distillation conditions (by concentrating the organic phase to minimum stir volume three times and thereafter adding 400 mL of ethanol following each step of concentrating). The final volume should be about 600 mL. The solution is warmed to 45°±5° C. and then water (834 mL) is added slowly to give a turbid system. The hazy slurry is cooled slowly to 5°±5° C., and held at that temperature for at least 16 hours. The resultant slurry is filtered, washed with 30% aqueous ethanol and then dried in a vacuum oven at 50° C. to yield 67.9 g of the desired sufentanil product (expected yield 84%; expected purity 99.7%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].Cl>O>[Cl:13][CH2:14][CH2:15][C:16]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[F:12])=[O:17]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCl)c1ccc(F)cc1F
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Aluminum chloride (0.3 mol) was added carefully to 1,3-difluorobenzene (0.26 mol) and the mixture was heated with vigorous stirring till 50° C. 3-Chloropropionyl chloride (0.26 mol) was added dropwise over a 15 min. period at 40° C. (cooled on ice) and the mixture was stirred at 50° C. The mixture was poured into water (250 ml), ice (250 g) and HCl (25 ml) and it was stirred for 20 min. The formed precipitate was filtered off and extracted with CH2Cl2 and water, yielding 40 g (75%) of 3-chloro-1-(2,4-difluorophenyl)-1-propanone (interm. 1).
Reaction SMILES: C([O:3][C:4]([CH:6]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1)=O)C.CN([BH3-])C.[Li+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:3][CH2:4][CH:6]([C:19]#[C:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]N(C)C
Solvent: C1CCOC1
Product: OCC(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 25 °C
Yield: 21.1 %

Procedure:
To 10 ml of tetrahydrofuran were added 200 mg of 4-[2-ethoxycarbonyl-4-phenyl-3-butynylamino]quinazoline and 1 ml of a lithium dimethylaminoborohydride solution (1 M in tetrahydrofuran), and the mixture was stirred at room temperature for an hour. To the reaction mixture, 20 ml of 1 N HCl was added and the mixture was stirred for 10 minutes. The reaction mixture was neutralized with an added aqueous solution of sodium hydrogencarbonate; thereafter, two extractions were conducted with 40 ml of ethyl acetate, followed by drying over sodium sulfate. After filtering the sodium sulfate, the organic layer was concentrated and purified by means of flash chromatography (Isolera™ manufactured by Biotage AB) to give 37 mg of 4-[2-hydroxymethyl-4-phenyl-3-butynylamino]quinazoline.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
Dimethylamine (100 mL of 2.0 M solution in tetrahydrofuran; 200 mmol) was added to a solution of 4-iodobenzenesulfonyl chloride (54.76 g; 181 mmol) in pyridine (300 mL) at 0° C. under N2, followed by the addition of 4-N,N-dimethylaminopyridine (15 mg). The reaction was allowed to warm to room temperature and was stirred under N2 for 48 hrs. The reaction solution was poured into 1.2 liter of water, and the precipitated product was collected by filtration and rinsed with water (300 mL×2). The solid was dissolved in ethyl acetate (500 mL) and washed with 5% aqueous hydrochloric acid (300 mL×3), water (300 mL×2) and brine (300 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to give 4-iodo-N,N-dimethyl-benzenesulfonamide (49.46 g; 88%) as a white solid, which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 2.69 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) was treated with benzoic acid 1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 mL, 11 mmol) and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, then dried over Na2SO4 and then evaporated under reduced pressure. The residue was subjected to mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give {1-[hydroxy-(N-benzoyloxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (850 mg) as a yellow solid. MS: MH+ 352.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([N:56]1[CH2:60][CH2:59][C@@H:58]([NH2:61])[CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:49]([N:56]1[CH2:60][CH2:59][C@@H:58]([NH:61][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 95 °C
Yield: 45.1 %

Procedure:
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (14.3 g) in dioxane (140 mL) was added palladium(II) acetate (1.52 g), 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (3.99 g), cesium carbonate (30.2 g), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (13.1 g), and the mixture was heated at 95° C. for 2.5 days. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with AcOEt to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as pale yellow oil (10.7 g)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].O.[NH2:14][NH2:15]>C(O)CO>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([CH3:11])=[N:14][NH:15]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: NN
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2′-fluoro-4′-methoxyacetophenone (0.5 g, 3.0 mmol) in ethylene glycol (10 mL) was added dropwise hydrazine hydrate (0.1 g, 3.1 mmol). The mixture was stirred for 24 h and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic layer was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give an orange oil. The oil was dissolved in ethylene glycol (10 mL) and heated at 165° C. for 24 h. The solution was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic extract was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)] to give the product (0.25 g, 51%) as a colourless solid: IR νmax (Nujol/cm−1) 1624, 1519, 1458, 1295, 1208, 1170, 1024 and 821; NMR δH (400 MHz, CDCl3) 2.54 (3H, s), 3.86 (3H, s), 6.78-6.81 (2H, m) and 7.52 (1H, d, J 9 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.[NH2:13][NH2:14]>C(O)CO>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:13][NH:14]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: OCCO
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 150 °C

Procedure:
100 g of 2-fluoro-4-methoxy-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150° C. for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave 6-methoxy-3-methyl-1H-indazole.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15].[Cl-].[NH4+]>CN(C=O)C.O>[CH3:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(C=O)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of 1H-indole-4-carbaldehyde (0.252 g, 1.72 mmol) in 8 mL of DMF was added sodium hydride (0.046 g, 1.9 mmol). After 5 min, iodomethane (0.13 mL, 2.1 mmol) was added. After 30 min, the reaction was treated with saturated aqueous ammonium chloride, diluted with water, and extracted 2× with dichloromethane. The combined organic fractions were washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes to provide 1-methyl-1H-indole-4-carbaldehyde that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 161.2 for [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([OH:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To a stirred solution of 1-{4-[1-Ethyl-1-(4-methyl-tliiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (5.2 g, 14 mmol) in THF/MeOH (40 ml/10 ml) at 0° C. is added NaBH4 (528 mg, 14 mmol), warmed to RT, and stirred for 1 h. The reaction is concentrated and the residue is partitioned between EtOAc and 0.2 N HCl. The organic layer is MgSO4 dried and concentrated to give the title compound (5.4 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[N:9]=[C:10]2[CH3:20]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Yield: 89 %

Procedure:
5-Amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole can be obtained as described in Example 6 from 3.4 g of N-tert-butoxycarbonyl-3-methyl-5-nitro-1H-indazole, 50 ml of methanol, 0.61 g of 10% palladium-on-charcoal and 3.53 g of ammonium formate. 2.7 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole are thus obtained in the form of a cream solid melting at 185° C.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>O1CCCC1>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(C)=O)C(C)=O
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Add pentane-2,4-dione (2.0 g, 20.6 mmol) in tetrahydrofuran (30 mL) to a chilled (0° C.) suspension of 60% sodium hydride (0.99 g, 24.7 mmol) in tetrahydrofuran (40 mL). Stir for 1 hr. Then add bromoacetic acid ethyl ester (2.73 mL, 24.7 mmol) in tetrahydrofuran (30 mL) dropwise. Stir at 0° C. to room temperature for 16 hr. Partition between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate organic layer, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 9:1 hexanes:ethyl acetate), to give 3-acetyl-4-oxopentanoic acid ethyl ester (3.34 g, 94%). 1H NMR (CDCl3) δ 5.15 (q, 2H), 5.1 (t, 1H), 2.84 (d, 2H), 2.23 (s, 6H), 1.22 (t, 3H).