Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: COC(C(=O)O)c1cccc2ncccc12
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(C(=O)N(C)OC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8 g, 12.9 mmol) in anhydrous CH2Cl2 (50 mL) and NMM (3.1 mL, 29 mmol) under argon was added isobutyl chloroformate (1.9 mL, 14 mmol) dropwise. After stirring over an ice bath for 40 min, N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 24 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-100% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide as an oil which became crystalline upon standing (1.8 g, 60% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11][Br:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)cccc1CBr
Temperature: 25 °C

Procedure:
2-Hydroxy-6-methyl-benzoic acid ethyl ester (4.046 g), NBS (4.786 g), and AIBN (1.134 g) were weighed into a round-bottom flask equipped with a reflux condenser. CCl4 (40 mL) was added and the mixture was heated at reflux for 2 h. After cooling to RT, solid was removed by filtration and the filtrate was concentrated to give a yellow oil as crude, which solidified upon standing. The crude was purified by silica gel chromatography (300 g, 0-5% EtOAc/hexanes) to afford 2-bromomethyl-6-hydroxy-benzoic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2D and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1COCC1.[Cu]I>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
1.15 g (1.63 mmol) of tetrakistriphenylphosphine palladium, 0.311 g (1.63 mmol) of copper (1) iodide, and 50 mL of triethylamine are added to a solution of 20 g (81.89 mmol) of 2,5-dibromopyridine in 250 mL of absolute THF under an argon atmosphere. At 17° C., a solution of 13 mL (90.14 mmol) of trimethylsilylacetylene in 20 mL of THF is immediately added dropwise to this reaction mixture. After ten minutes, the cooling is removed. After 20 minutes, the temperature is 30° C. The mixture is then cooled to 20° C. and briefly stirred. The reaction mixture is evaporated down, the residue is taken up in ethyl acetate and extracted twice with sodium hydrogen carbonate solution. The combined organic phases are dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether). Yield: 20.4 g (98% of theory); C10H12BrNSi (M=254.20); calc.: molecular ion peak (M+H)+: 254/256; found: molecular ion peak (M+H)+: 254/256; Rf value: 0.72 (silica gel, petroleum ether).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20]CC=C)[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:6]=1)(=[O:3])[CH3:2].C1([SiH3])C=CC=CC=1>ClCCl.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:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([OH:20])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(NC(C)=O)c(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2CCCC2)c2c(Cl)ccc3c2c1C(=O)N(O)C3=O
Reaction time: 1 h

Procedure:
A solution of 4-acetylamino-2-allyloxy-7-chloro-6-(pyrrolidin-1-yl)benzo[de]isoquinoline-1,3-dione (0.24 g, 0.6 mmol, from Example H4) and phenylsilane (0.13 g, 1.2 mmol) in 15 mL of dichloromethane was cooled to 15° C. and treated with tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol). The reaction was stirred for 1 hour and the solvent removed in vacuo. The residue was dissolved in methanol, filtered, and evaporated in vacuo. The residue was stirred with ether to give a fine precipitate which was filtered, washed with ether, and dried in vacuo to give 0.1 of the title compound, mp 152-154° C.
Reaction SMILES: C(OP([CH:9]1[S:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.CCCCCC.C([Li])CCC.[CH:25]1[CH:30]=[CH:29][C:28]([C:31]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=O)=[CH:27][CH:26]=1.[Cl-].[Na+]>O1CCCC1>[O:35]([C:34]1[CH:26]=[CH:27][C:28]([C:29](=[C:9]2[S:10][CH2:11][CH2:12][S:13]2)[CH2:30][CH3:25])=[CH:31][CH:33]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)C1SCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=C1SCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiolan, 3.0 g, was dissolved in 30 ml of tetrahydrofuran and 7.75 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 2.55 g of 4-phenoxypropiophenone in 9 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution and the mixture was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 2.60 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.05 h
Yield: 63.2 %

Procedure:
40% Methanolic Triton B (0.086 mL, 0.19 mM) was added to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) Was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 44.0 mg (63%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1746, 1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=2[CH:41]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:27][C:28]2[CH:29]=[CH:30][C:31]3[C:37]([CH3:38])([CH3:39])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=3[CH:41]=2)=[N:3][CH:4]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)ccc21
Yield: 76 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (88 mg, 0.22 mmol), 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg, 0.22 mmol), and 10-Camphorsulfonic acid (7.8 mg, 0.033 mmol) in Isopropyl alcohol (2 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.25 mL satd. sodium bicarbonate, stirred for 10 min, then cooled for 1 h. The resultant solids were collected, washing with water, drying in vacuo to afford 3-{2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-5-morpholin-4-yl-phenoxy}-propionitrile as dark yellow solids (94 mg, 75%). MP: 150-156° C., LCMS 562 (M+H), 1H-NMR (CDCl3): 8.00 (d, 1H, J=8.9 Hz), 7.98 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.04 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.61 (d, 1H, J=8.8 Hz), 6.52 (s, 1H), 4.27 (t, 2H, J=6.2 Hz), 3.90 (t, 4H, J=4.7 Hz), 3.23 (t, 4H, J=4.7 Hz), 2.87 (t, 2H, J=6.2 Hz), 2.38 (t, 2H, J=7.0 Hz), 2.09 (t, 2H, J=7.0 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]#[N:12])=[N:7][C:8]=1[CH2:9]Br.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1=[N:7][C:6]([C:11]#[N:12])=[CH:5][CH:4]=[C:3]1[CH2:2]2
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: N#Cc1ccc(CBr)c(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(C#N)nc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 5,6-bis(bromomethyl)pyridine-2-carbonitrile from Step C (1.80 g, 6.21 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.64 g, 6.21 mmol, described in Intermediate 7) in DMF (207 mL) was added cesium carbonate (6.07 g, 18.6 mmol), portionwise, over 5 min. After 18 h, the mixture was partitioned between CH2Cl2 (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (200 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 10:90, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:21]([C:34](OCC)=[O:35])=[CH:20]2.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([NH:5][C:34]([C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([F:16])=[CH:25][CH:24]=3)=[O:35])[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc2ccccc2c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cnc2ccccc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
1.19 mL (2.38 mmol) of a 2M solution of trimethylaluminium in toluene are added dropwise to a solution, stirred at 0° C. under an inert atmosphere, of 0.274 g (1.9 mmol) of 3-aminoquinoline in 40 mL of dry toluene. The mixture is then stirred at 50° C. After 15 minutes, a solution of 0.5 g (1.59 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in 10 mL of toluene is added dropwise. 15 mL of 1N hydrochloric acid solution and 100 mL of ethyl acetate are added to the mixture. The organic phase is separated out and then washed successively with 20 mL of 1N hydrochloric acid solution, 20 mL of water and 20 mL of saturated sodium chloride solution, and then concentrated under reduced pressure. The product thus obtained is triturated in 10 mL of hot toluene. A precipitate is collected by filtration. After drying, 295 mg of the expected product are thus isolated.
Reaction SMILES: [CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10][NH:28][C:25]2[N:26]=[N:27][N:23]([CH3:22])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1C=O)C1CCCCC1
Reactant: Cn1nnc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(c1ccc(C(F)(F)F)cc1CNc1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzaldehyde (90 mg, 0.30 mmol) and 2-methyl-2H-tetrazol-5-amine (35.6 mg, 0.36 mol) in toluene (1.5 ml) was heated at 50° C. for overnight. Solvent was removed in vacuo and reaction mixture was diluted with ethanol (2 ml) and treated with sodium borohydride (21.8 mg, 0.577 mmol) and stirred at room temperature for overnight. Reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 ml) and washed with water (30 ml). Organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The crude product was purified on Biotage column (12+M), eluting with 7% ethyl acetate in heptane (1 CV), 7-60% (10CV), 60% (2CV) to yield the title compound (65 mg, 58%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 4H) 1.25 (s, 2H) 1.62 (m, 3H) 1.76 (m, 1H) 1.99 (d, J=14.1 Hz, 1H) 3.16 (s, 3H) 4.13 (s, 3H) 4.2 (d, J=7.5 Hz, 1H) 4.48 (dd, J=5.4 Hz, 1H) 4.65 (dd, J=6.6 Hz, 1H) 4.93 (m, 1H) 7.47 (d, J=7.8 Hz, 1H) 7.54 (d, J=8.3 Hz, 1H) 7.67 (s, 1H). MS (ES+) Calc: 383.4, Found: 349.3 (M−34).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:12])[C:4]=2[O:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:28])=S.[Na+].[Na+]>C(OCC)(=O)C>[O:28]1[C@H:6]2[C@@H:7]1[C:2]([CH3:16])([CH3:1])[O:3][C:4]1[C:11]([CH3:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:5]=12
Reactant: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)C=C2
Reactant: O=S([O-])([O-])=S
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@@H]1O[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution (50 mL) of ethyl acetate containing 2,2,8-trimethyl-7-nitro-2H-1-benzopyran (3.32 g, 15.1 mmol), N-methyl imidazole (0.482 mL, 6.05 mmol) and (R,R,S,S)-Ph,Ph salen manganese complex (XY) (142 mg, 0.151 mmol) were added at room temperature, and sodium hypochlorite aqueous solution (34.1 mL, 1.776 mol/kg, 60.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting solution was filtered through celite. The resulting filtrate extracted with ethyl acetate. The organic phase was washed with water and sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=7/1) and the aimed product was obtained as pale yellow crystal (yield: 78%, optical purity: 99% ee).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=O)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:19].N1CCCCC1>CO>[C:18](/[C:20](=[CH:9]\[C:8]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])/[C:21]([O:23][CH3:24])=[O:22])#[N:19]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Yield: 27.1 %

Procedure:
To a mixture of 3.00 g (11.58 mmol) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde and 1.5 mL (16.95 mmol) of methyl cyanoacetate in 30 mL of methanol is added 0.3 mL of piperidine. The mixture is heated at reflux for 5 minutes then cooled slightly and the thick suspension is collected by filtration washing with ethyl acetate followed by diethyl ether to give 1.07 g (27%) of methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate as a yellow solid, mp softens at 121° C., melts at 157–160° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:22][CH2:23]O)[C:16]=3[CH:15]=[N:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[N:13]([C:8]3[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=3)[N:14]=[CH:15][C:16]1=2
Reactant: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 85 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (512 mg, 1.65 mmol) in 20 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (462 mg, 1.40 mmol, 85%, oil).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(C#N)c(O)n1
Product: CSc1ncc(C#N)c(Cl)n1

Procedure:
A mixture of 4-hydroxy-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.76 g) and phosphorus oxychloride (15 mL) was heated at reflux, under argon atmosphere, for 3 h. The reaction mixture was cooled and then evaporated under reduced pressure. Hexane was added to the residue and the mixture was heated at reflux, the resulting mixture was decanted and the same procedure was repeated for 4 times. The combined supernatant layers were evaporated to afford 1.13 g of 4-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile as a white powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]3[S:20][C:21]([NH2:23])=[CH:22][C:15]=23)=[CH:11][CH:10]=1.Cl>C(O)=O>[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]3[S:20][C:21]([NH:23][CH:1]=[O:3])=[CH:22][C:15]=23)=[CH:11][CH:10]=1
Reactant: Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=CO
Product: O=CNc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 70 °C
Reaction time: 96 h
Yield: 49 %

Procedure:
A mixture of 5 mL of acetic anhydride and 1.8 mL of 96% formic acid was heated to 70° C. for 3 hours. The solution was allowed to cool whereupon the obtained amine from Example 263 (32 mg, 0.12 mmol) was added. The mixture was stirred for 4 days and then poured into 50 mL of dilute HCl. The mixture was extracted with ethyl acetate, the combined extracts were washed with saturated sodium carbonate and then water, dried (MgSO4), and evaporated. Purification of the resulting product by preparative HPLC using a gradient of 30%-70% acetonitrile/water +0.1% TFA over 40 minutes afforded 18 mg (49%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.CCO.[C-:16]#[N:17].[K+]>O>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]#[N:17]
Reactant: [C-]#N
Reactant: Cc1cccc(CBr)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(CC#N)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 93.9 %

Procedure:
A round bottomed flask was charged with 6.51 g (0.028 mol) of 3-methyl-2nitrobenzyl bromide, 120 mL 1:1 EtOH:H2O, and 5.5 g KCN (0.084 mol). The reaction solution was heated to 60° C. for 2 h. The reaction was cooled and the volatiles removed in vacuo. The resulting solid was dissolved in 150 mL water and extracted with 300 mL ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. This gave 4.63 g (92% yield) of the desired material as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.33–7.31 (m,1H), 3.77 (s, 2H), 2.36 (s, 3H).