Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH3:16])[CH2:13][C:12]1([Cl:15])[Cl:14]>C1(CCO)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH3:16])[CH2:13][C:12]1([Cl:14])[Cl:15])[NH2:17]
Reactant: CC1(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1(Cl)Cl
Solvent: OCCc1ccccc1
Product: CC1(CCOc2ccc(N)cc2Cl)CC1(Cl)Cl
Yield: 91.8 %

Procedure:
A suspension of 12 g of 3-chloro-4-[2-(1-methyl-2,2-dichlorocyclopropyl)ethoxy]nitrobenzene and 0.1 g of platimum dioxide in benzene-ethanol (1:1) was subjected to catalytic reduction under room temperature and atmospheric pressure, whereby 2.5 liters of hydrogen were absorbed. The resulting mixture was filtered, and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give 10 g of 3-chloro-4-[2-(1-methyl-2,2-dichlorocyclopropyl)ethoxy]aniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]=[C:5]([C:7]1[N:8]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]2[C:14]([CH:15]=1)=[C:13](Br)[CH:12]=[CH:11][CH:10]=2)[CH3:6].[CH2:27]([O:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35]([CH:41]([CH3:43])[CH3:42])=[CH:34][C:33]=1B(O)O)[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]=[C:5]([C:7]1[N:8]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]2[C:14]([CH:15]=1)=[C:13]([C:33]1[CH:34]=[C:35]([CH:41]([CH3:43])[CH3:42])[CH:36]=[C:37]([CH:38]([CH3:39])[CH3:40])[C:32]=1[O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=[CH:11][CH:10]=2)[CH3:6]
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: COC(=O)C=C(C)c1cc2c(Br)cccc2n1S(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)OC)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
3-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)-but-2-enoic acid methyl ester (117 mg, 0.27 mmol) and 2-butoxy-3,5-diisopropylphenyl-boronic acid (150 mg, 54 mmol) (see Example 17, step B) were dissolved in toluene (2 mL) under a nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (31 mg, 0.027 mmol) and 2N Na2CO3 (0.7 mL) were added and the biphasic mixture stirred at 75° C. for 16 h. The reaction was diluted with water/ethyl acetate. The layers were separated and the aqueous layer was washed with ethyl acetate. The organic portions were passed through a pad of Celite, dried (MgSO4), filtered and concentrated in vacuo to provide 243 mg of a crude black oil. Radial chromatography using (99:1) hexane:ethyl acetate provided 76 mg (48%) of product. 1H NMR (250 MHz, CDCl3): δ 8.15 (d, 1H, 8.2), 7.66 (m, 2H), 7.46-7.27 (m, 5H), 7.11 (d, 1H, J=2.2), 6.90 (d, 1H, J=2.2), 6.54 (s, 1H), 6.05 (d, 1H, J=1.2), 3.80 (s, 3H), 3.36 (sep, 1H, J=6.9), 3.04 (t, 2H, J=6.0), 2.88 (sep, 1H, J=6.9), 2.61 (d, 3H, J=1.2), 1.25 (d, 6H, J=6.9), 1.24 (d, 6H, J=6.9), 1.08-0.87 (m, 4H), 0.62 (t, 3H, J=7.0). MS [EI+] 588 (M+H)+ [EI−] 586 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14]Br)=[CH:6][CH:5]=1>C(O)C(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][O:2][CH2:3][CH:4]([CH3:9])[CH3:5])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCC=C(C)CBr)cc1
Solvent: CC(C)CO
Product: COC(=O)c1ccc(OCC=C(C)COCC(C)C)cc1

Procedure:
A solution of 6.0 g (0.02 mol) of 4-(4-bromo-3-methyl-2-butenyloxy)-benzoic methyl ester and 2.9 g (0.03 mol) of sodium-isobutylate in 130 g of isobutanol is stirred at 70° for 6 hours. After this period the reaction mixture is filtered, the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, the ether solution is washed with saturated salt solution, dried with sodium sulphate and evaporated. The residue (6.5 g) is dissolved in 50 cc of absolute methanol, 0.54 g (0.01) mol of sodium methylate is added and the mixture is boiled under reflux for 2 hours. After this period 40 cc of methanol are distilled off. The remaining residue is dissolved in 100 cc of ether, the ether solution is extracted twice with 100 cc amounts of saturated salt solution and dried with sodium sulphate. The ether is distilled off and the resulting 4-(4-isobutoxy-3-methyl-2-butenyloxy)-benzoic methyl ester is purified by chromatography on silica gel with hexane/ethyl acetate 20:1. nD20 = 1.5151.
Reaction SMILES: [C:1]([CH2:4][N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([OH:3])=O.Cl.[CH3:20][NH:21][CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[CH3:20][N:21]([CH3:22])[C:1]([CH2:4][N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.0 g of N-carboxymethyl-N-methylsulphonyl-4-nitroaniline, 2.5 g of dimethylamine hydrochloride, 8.1 g of TBTU and 3.9 g of HOBT are dissolved in 125 ml of dimethylformamide and at 0° C. 17.6 ml of N-ethyl-diisopropylamine are added. The mixture is stirred for 4 hours at ambient temperature, diluted with 1 l water and the precipitate formed is suction filtered. After washing with water, ethanol and ether the residue is dried at 70° C. in vacuo.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3]1.Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24]N)=[CH:23][C:18]=2[O:17][CH2:16]1.Cl>O>[O:17]1[C:18]2=[CH:23][C:22]3[NH:24][C:2]4[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][C:3]=4[C:21]=3[CH:20]=[C:19]2[O:15][CH2:16]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Agent: Cl
Solvent: O
Product: CC(C)C(=O)NC1CCc2[nH]c3cc4c(cc3c2C1)OCO4
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Add N-(4-oxo-cyclohexyl)-isobutyramide (974 mg, 5.32 mmol) a suspension of benzo[1,3]dioxol-5-yl-hydrazine hydrochloride salt (Clemo, G. R.; Weiss, J. J. Chem. Soc. (1945), 702.) (1.00 g, 5.32 mmol) to water (7 mL) and concentrated hydrochloric acid (3 mL). Heat the reaction to 90° C. for 12 h and cool to ambient temperature. Collect the resultant solid by vacuum filtration, rinse with water and place under high vacuum for 12 h to afford the titled compound (1.20 g, 75%) as a dark brown solid. m.p.=198-200° C.; 1H NMR (300 MHz, CDCl3): δ 7.77 (br s, 1H), 6.81 (s, 1H), 6.78 (s, 1), 5.91 (s, 2H), 5.57 (br s, 1H), 4.40 (br s, 1H), 3.00 (dd, J=15.4, 5.1 Hz, 1H), 2.80-2.69 (m, 2H), 2.50 (dd, J=15.4, 6.5 Hz, 11H), 2.30 (septet, J=6.9 Hz, 1H), 2.05-1.96 (m, 2H), 1.14 (d, J=6.9 Hz, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:24][CH3:25])[CH:10]=2)[N:5]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].ClCCl>O>[CH2:28]([N:30]([CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:24][CH3:25])[CH:10]=2)[N:5]=1)[CH2:31][CH3:32])[CH3:29]
Reactant: CCNCC
Reactant: COc1ccc(-c2nc(CCBr)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Yield: 8.4 %

Procedure:
A mixture of 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.486 g), diethylamine (0.41 g) and dichloromethane (10 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform - ethyl acetate (1:1, v/v) gave 2-[2-(N,N-diethylamino)ethyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.040 g, 8%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[NH:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:51]3[CH2:56][CH2:55][S:54][CH2:53][CH2:52]3)=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Reactant: C1CSCCN1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCSCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(3-chlorophenyl)amino]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (0.2 g) in dimethylformamide (5 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.15 g), 1-hydroxybenzotriazole (0.14 g), N-ethylmorpholine (0.34 ml) and thiomorpholine (0.13 ml). The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium bicarbonate solution followed by saturated sodium chloride solution then dried (MgSO4) and evaporated. The residue was purified by MDAP to afford the title compound as a white solid (236 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:14].CN1CCCN(C)C1=O.Br[CH2:35][CH2:36][Cl:37]>C1COCC1.C(OCC)C>[CH2:13]([O:15][C:16](=[O:24])[CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:35][CH2:36][Cl:37])[CH3:14]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: ClCCBr
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.71 ml, 1.1 eq) was added to dry THF (10 ml) and cooled to -78° C. N-butyllithium (11.01 ml of 1.6 Molar, 1.1 eq) was added dropwise. The mixture was stirred at -78° C. for 30 minutes and ethyl-2-phenylacetate (2.9 g, 1.0 eq) was dissolved in dry THF (20 ml) and the solution added dropwise to the reaction mixture. The mixture was stirred at -78° C. for 0.25 hour and then allowed to warm to -30° C. and stirred for an additional 0.25 hour. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (2.13 ml, 1.0 eq) was dissolved in dry THF (20 ml) and added dropwise to the mixture. The resulting mixture was maintained at -30° C. for ten minutes. This mixture was then cannulated under N2 pressure to a flask which had been charged with ethyl ether (100 ml) and 1-bromo-2-chloroethane (7.3 ml, 5.0 eq) at -10° C. The mixture was stirred for three hours at -10° C. to -5° C. The mixture was cooled to -30° C. and quenched with a saturated ammonium chloride solution. The mixture was extracted with ethyl ether which was then dried over K2CO3. The solvent was stripped to provide 3.2 g of product which distilled at 70°-71° C. under 0.01 mmHg.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:29]([C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)=[O:30])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene and 4-fluorobenzoyl chloride by essentially following the procedure detailed in Example 129, Part A.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloronicotinamide (5.00 g, 31.95 mmol), 4-fluorobenzene boronic acid (4.92 g, 35.14 mmol), and Pd(PPh3)4(1.10 g, 0.96 mmol) in a mixture of toluene (80 ml), ethanol (12 ml) and 2M sodium carbonate (36.74 ml, 73.48 mmol) was degassed (N2) and heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried. The dried solid was taken up in methanol (100 ml) and heated to reflux for 20 minutes. The mixture was then cooled to room temperature, filtered and the solid dried to give the title compound (6.25 g, 90%) as a pale grey solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCNCC3)s2)s1

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (280 mg; 0.84 mmol; 1 eq), is dissolved in DCM (10 ml). N-Methyl piperazine (1.4 g; 16.8 mmol; 20 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one night reaction, water (1 ml) is added and the solvents evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (11) as a white solid (125 mg; 40%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:11]=2)[CH2:2]1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:11]=2)[CH2:2]1
Reactant: c1cc(-c2n[nH]c3ccc(-n4cc([C@@H]5CCCNC5)nn4)cc23)ccn1
Reactant: O=Cc1c(F)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Fc1cccc(F)c1CN1CCC[C@@H](c2cn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)nn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To (R)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.075 g, 0.2 mmol) dissolved in MeOH (3 mL) at 0° C. was added 2,6-difluorobenzaldehyde (0.29 g, 2.1 mmol) and then sodium triacetoxyborohydride (0.11 g, 0.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Evaporated the solvent, subjected to Preparative Thin Layer chromatography to give (R)-5-(4-(1-(2,6-difluorobenzyl)piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.025 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](\[C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])/[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromo-1-methyl-vinyl)-2,4-difluoro-benzene (279 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-2% MeOH-DCM. The product was further purified by HPLC. Yield: 23 mg. 1H NMR (CD3OD, freebase) δ (ppm): 7.27 (d, 1H), 7.00 (m, 2H), 6.93 (dd, 1H), 7.83 (d, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 3.52 (s, 2H), 2.80 (t, 2H), 2.70 (t, 2H), 2.50 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH3:20][C:21]1[O:14][C:13]([C:12]2[CH:17]=[CH:18][N:19]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[CH:11]=2)=[N:15][N:16]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CSc1ccc(Nc2cc(C(=O)NN)ccn2)cc1
Product: CSc1ccc(Nc2cc(-c3nnc(C)o3)ccn2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide (511 mg, 1.86 mmol) and triethyl orthoacetate (10 mL) was stirred at 120° C. overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (441 mg, yield 80%) as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC1C=CC=CC=1Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: c1ccc(-c2ccco2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-Phenyl-furan (119)(50 mg, 0.28 mmol) and (3-bromo-phenyl)-acetic acid (134 mg, 0.63 mmol) were dissolved in ortho-dichlorobenzene (4 ml). P2O5 (202 mg, 1.42 mmol) was added as a suspension in ortho-dichlorobenzene (2 ml). The reaction mixture was heated to 80° C. for 2 h and cooled to room temperature overnight. After the addition of further P2O5 (202 mg, 1.42 mmol), heating was resumed at 90° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched with H2O (15 ml). The organic layer was separated and the aqueous layer was washed with DCM (3×10 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted with 10% EtOAc in heptane.
Reaction SMILES: C([N:8]([C@@H:24]([C:33]1[O:34][CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9](=[O:23])[C@H:10]([NH2:22])[CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:22][C@H:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:9]([NH:8][C@@H:24]([C:33]1[O:34][CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23]
Reactant: CCOC(=O)c1coc([C@@H](CCc2ccccc2)N(C(=O)OC(C)(C)C)C(=O)[C@H](N)CCCNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1coc([C@@H](CCc2ccccc2)NC(=O)[C@H](N)CCCN)n1

Procedure:
A solution of ethyl 2-[(1R)-1-[(2R)-N,N′-bis-Boc-2,5-diaminovaleramido]-3-phenylpropyl]-4-oxazole-carboxylate (67 mg) and trifluoroacetic acid (1 mL) was kept at 25° C. for 1 hr, concentrated in vacuo and coevaporated with toluene. The residue was purified further by reverse phase chromatography (20 mL Amberchrom, 0% to 50% CH3CN in 0.1% aqueous TFA over 45 min. at 2 ml/min. flow-rate) to give the desired compound (60 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 1.41 (t, J=7.1 Hz, 3H), 1.80 (m, 2H), 2.02 (m, 2H), 2.39 (m, 1H), 2.46 (m, 1H), 2.80 (m, 1H), 2.87 (m, 1H), 3.10 (t, J=7.4 Hz, 2H), 4.17 (t, J=6.4 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 5.14 (t, J=7.0 Hz, 1H), 7.32 (m, 3H), 7.41 (m, 2H), and 8.48 (s, 1H).
Reaction SMILES: [Na].[CH2:2]([OH:16])[C@@H:3]([OH:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]([OH:11])[C:8]([O-:10])=[O:9].[Na+]>O.O[W](O)(=O)=O>[CH2:2]([OH:16])[C@@H:3]([OH:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]([OH:11])[C:8]([OH:10])=[O:9]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=[W](=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
The tungsten ester of glucoheptonic acid was prepared as follows: Approximately 330 grams (1 mol) of the sodium salt of tungstic acid (sodium tungstate) and 248 grams (1 mol) of sodium glucoheptonate were charged to an esterification vessel containing about 600 ml. of water as a solvent. With stirring, the temperature was maintained at about 25° C. for approximately 30 minutes. The mixture was thereafter diluted to a final volume of one liter with additional water.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH2:19]([NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CN
Reactant: CC1SC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC#N
Product: CC(C)CNc1ccc(C2=NNC(=O)SC2C)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.6 %

Procedure:
To 15 ml of acetonitrile are added 2.9 g (10.1 mM) of 5-(4-chloro-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 5 ml (50 mM) of isobutylamine. The reaction medium is maintained at 60° C. for 20 hours with stirring and is then concentrated under vacuum. The residue obtained is purified on silica using dichloromethane as eluent. The product obtained is taken up and crystallised from diethyl ether. The solid is filtered off and washed to give 2.6 g of 5-[4-(isobutylamino)-3-nitrophenyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.