Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cc(OCCN3CCCC3)ccc2C)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: CO
Product: Cc1ccc(OCCN2CCCC2)cc1-c1c(-c2ccc(O)cc2)ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of the product of Example 18 (1.61 g, 2.60 mmol) in 1.2-dichloroethane (30 mL) stirring at 0° C. was added boron trichloride (10 ml, 117 mmol). The resulting dark purple solution was stirred overnight at ambient temperature in a sealed tube. After cooling the solution to 0° C., methanol (25 mL) was carefully added over a period of 30 minutes (caution, gas evolution). The solution was subsequently concentrated and the resulting material dissolved in 30% isopropanol/chloroform then washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by radial chromatography (methanol/chloroform gradient) to give 0.34 g (27%) of the desired product as a white foam: 1H-NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.36 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.00-7.10 (m, 2H), 6.80-6.90 (m, 2H), 6.70-6.80 (m, 4H), 5.45 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.90-4.05 (m, 2H), 2.75-2.90 (m, 2H), 2.50-2.65 (m, 4H), 1.60-1.80 (m, 4H); 13C-NMR (75 MHz, DMSO-d6) δ 203.32, 191.97, 188.16, 186.14, 185.95, 177.43, 173.46, 169.60, 167.74, 163.48, 162.30, 159.87, 158.14, 154.98, 152.43, 60.50, 56.25, 54.00, 45.05, 41.00, 37.50, 35.00, 30.05, 27.50, 26.00, 22.50, 20.00; Anal. Calc'd. for: C, 79.24; H, 6.65; N, 3.19. Found: C, 78.99; H, 6.51; N, 2.92; MS (FD) m/e 440 (M+); IR (KBr) 3382.61, 2964.00, 1610.77, 1509.49 cm−1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>>[CH2:11]([C:4]1[S:3][C:2]2[N:1]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:21]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCCCc1cc(C(=O)OC)c(N)s1
Product: CCCCc1cc2c(=O)n3cc(C(=O)OC)ccc3nc2s1
Yield: 42.1 %

Procedure:
From 5.1 g (0.024 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, methyl ester and 4.1 g (0.024 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company), following the procedure of Example 7, there is obtained 3.2 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester; mp 137°-138° C. after recrystallization from methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCNCC
Product: CCN(CC)c1ccc([N+](=O)[O-])cn1

Procedure:
Following Intermediate Method 5, the reaction of 2-chloro-5-nitropyridine, (XXII) with diethylamine produces 2-diethylamino-5-nitropyridine, (XXII). The reduction of this compound (XXII) with iron powder in aqueous hydrochloric acid and ethanol yields 5-amino-2-diethylaminopyridine, (XXIII).
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[F:16][C@H:17]1[CH2:21][NH:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCO>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][C@H:18]2[C@@H:17]([F:16])[CH2:21][N:20]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](F)C3)c2n1
Yield: 34.2 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.26 g, 1.28 mmole) in EtOH (5 mL) was added (±)-phenylmethyl {[cis-4-fluoro-3-pyrrolidinyl]methyl}carbamate (0.32 g, 1.28 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (0.20 g, 34%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(F)ccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,5-difluoroaniline to yield 2-[(2,5-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl.[CH3:2][NH:3][C@@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].Br[CH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1>>[CH3:2][N:3]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:24][CH:25]=1)[C@@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CN[C@@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: Cl
Product: CC(C)[C@H](C(=O)O)N(C)Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 74 %

Procedure:
Prepared by reaction of methyl D-valine hydrochloride and tert-butyl 4-bromomethylbenzoate analogously to Example 56, stage a. The compound was obtained in 74% yield after chromatographic purification, FAB-MS: 321 (M+).
Reaction SMILES: Cl.[CH3:2][C:3]([Si:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:5])[CH3:4].C(N(CC)C(C)C)(C)C.[CH3:24][C:25]([O:28][C:29]([N:31]1C(C2C=CC(C#N)=CC=2)O1)=[O:30])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:28][C:29]([NH:31][N:11]([CH2:10][CH2:9][CH2:8][O:7][Si:6]([C:3]([CH3:2])([CH3:4])[CH3:5])([CH3:13])[CH3:14])[CH3:12])=[O:30])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CNCCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-N-methyl-1-propanamine hydrochloride (1:1) (720 mg, 3.0 mmol) was combined with dichloromethane (30 mL) to give a colorless solution. N,N-Diisopropylethylamine (313 mg, 423 μl, 2.42 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (542 mg, 2.2 mmol) in dichloromethane (20 mL) was added during 15 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 70% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 20 g, ethyl acetate/n-heptane 1/1) to give the title compound as colorless oil.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:19]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])=[C:14]([CH:18]=1)[C:15](O)=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:73]([NH2:84])[C:74]1[CH:83]=[CH:82][C:79]([O:80][CH3:81])=[C:76]([O:77][CH3:78])[CH:75]=1>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:19]([C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])=[O:21])[CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[C:14]([C:15](=[O:16])[NH:84][CH2:73][C:74]2[CH:83]=[CH:82][C:79]([O:80][CH3:81])=[C:76]([O:77][CH3:78])[CH:75]=2)[CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)COC(=O)N(c1ccc(OCc2ccccc2)cc1C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2N(C(=O)OCC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Reaction time: 0.25 h

Procedure:
A mixture of 6 g of sodium salt of 5-(benzyloxy)-2-({1-[(1,1-dimethylethoxy)carbonyl]piperidin-4-yl}[(2-methylpropoxy)carbonyl]amino)benzoic acid obtained in stage 1.3 and 4.42 g of DIEA in 250 ml of DMF is stirred at AT for 15 min. 6.48 g of HBTU are added and the mixture is left stirring for 30 min. 2.48 g of veratrylamine are added and the reaction mixture is stirred for 48 h 00. It is evaporated under reduced pressure, the residue is taken up in AcOEt, washed with a saturated NH4Cl solution and with a saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (20/80, v/v) as far as (60/40, v/v), to give 7.5 g of expected product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octyl chloroformate (85 g) under ice cooling, heating on a water bath, allowing the reaction mixture to stand overnight, adding toluene (300 ml) and 6N hydrochloric acid, separating the liquid layer, further washing with an aqueous solution of 2N NaOH, washing with water, drying and distilling off toluene to obtain a raw product of p-octyloxycarbonyloxybenzaldehyde (75 g).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH2:2][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1

Procedure:
In 100 ml of ethanol was dissolved 4.2 g (1.1 eq.) of sodium, and a mixture of 25.0 g of 4-methoxyacetophenone and 27 ml (1.2 eq.) of diethyl oxalate was added dropwise under reflux. After 2 hours' reflux, the resulting crystals were collected by filtration. After 200 ml of 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>O1CCCC1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:32]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:41])=[CH:35][CH:36]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Oc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.30 mL, 1.7 mmol) and 4-fluorophenyl chlorocarbonate (45 mg, 0.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and crystallized from diisopropyl ether to obtain the title compound (58 mg, yield 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].O1CCOCC1.C([O-])(O)=O.[Na+]>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.CCOC(C)=O>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][CH3:14])[N:5]=1
Reactant: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1CCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To 4-chloro-6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-pyrimidinamine (40 mg, 0.176 mmol) and (4-cyano-3-fluorophenyl)boronic acid (29.1 mg, 0.176 mmol) was added 1,4-dioxane (3 mL) followed by sat. aq. NaHCO3 (0.5 mL), and the mixture was purged with N2 for 10 minutes into a sealable tube. Pd(Ph3P)4 (20.4 mg, 0.018 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100° ACHCl3 to 95:5:0.5 CHCl3:CH3OH:NH4OH) afforded the title compound (52 mg) as a solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[OH:2][CH2:1][CH2:3][NH:4][C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5]
Reactant: NCCO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
23 ml (0.38 mmol) of ethanolamine were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 41.44 g (0.29 mol, 80% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
To a stirred solution of 4-chloro-3-nitroaniline (17.3 g, 100 mmol) in DCM (150 mL) was added dropwise acetic anhydride (14 mL, 150 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2.5 h. The solvent was removed in vacuo, and Et2O was added to the residue. The precipitate was collected by filtration, washed with Et2O, and dried in vacuo to give N-(4-chloro-3-nitrophenyl)acetamide (20.7 g, 96%), which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N+:8]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([O:18]C(C)=O)=[O:17]>>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:18][C:16](=[O:17])[CH3:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(-c2ccccc2)[n+]1[O-]
Product: CC(=O)OCc1cccc(-c2ccccc2)n1
Yield: 70 %

Procedure:
A stirred solution of the crude 2-phenyl-6-methyl-pyridine-N-oxide (5.2 g, 28.5 mmol) in Ac2O (25 ml) was heated at reflux temperature for 2 hrs. The Ac2O was removed with the aid of an oil pump (10 mm) at 40° C. to yield a red oil which was purified by flash chromatography over silica gel with Et2O/petroleum benzine=1/1 as the eluent and yielded 2-phenyl-6-(acetoxymethyl)-pyridine (4.6 g, 70%) as an oil.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.O>CCO>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[N:4]=1
Reactant: ClCCCc1c[nH]cn1
Reactant: Nc1cc[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccnc(SCCCc2c[nH]cn2)n1

Procedure:
A mixture of thiocytosine (0.7 g.), sodium hydroxide(0.22 g.) and 4-(3-chloropropyl)imidazole (0.8 g.) was stirred in EtOH (8 ml.) and water (8 ml.) at room temperature for 16 hours and then heated under reflux for 2 hours. The solution was evaporated to dryness and the residue partitioned between dilute aqueous sodium hydroxide (20 ml.) and EtOAc (30 ml.). The EtOAc layer was evaporated to dryness to give 4-[3-(4-aminopyrimid-2-ylthio)propyl]imidazole as a brown gum which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-nitrobenzaldehyde (115 g) and hydroxylamine hydrochloride (6.6 g) in ethanol (110 ml) and water (4 ml) was added sodium acetate (13.6 g) and the mixture was stirred at room temperature for 4 hours. The mixture was poured into water (500 ml) and the mixture filtered to give the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1Cc1ccccc1

Procedure:
A solution of 2-[4-benzyloxy-2-(hydroxy-phenyl-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester (1.67 g, 3.97 mmol maximum) in ethanol (50 mL) was treated with 5% Pd/C (0.42 g) and hydrogen (60 psi, rt, 18 h). The mixture was filtered and concentrated to a viscous colorless oil (1.15 g, 91%): 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 3.99 (s, 2H), 4.30 (q, 2H, J=7.0 Hz), 4.93 (brs, 1H), 6.58-6.66 (m, 3H), 7.22-7.34 (m, 5H); MS (ES) m/e 315 [M+1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[N:7]1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: COC(=O)c1cc(-c2cn[nH]c2)cc2c1c(C)nn2C(C)C
Temperature: 115 °C

Procedure:
The title compound was prepared in the same manner as described for example 80 (step a) from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (0.5 g, 1.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.37 g, 1.92 mmol) wherein the reaction mixture was heated at 115° C. for 3 h. The crude compound was purified silica gel chromatography (eluent: 50% ethyl acetate\pet ether) to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.470 (d, J=6.4 Hz, 6H), 2.543 (s, 3H), 3.928 (s, 3H), 5.000-5.063 (m, 1H), 7.822 (s, 1H), 8.102 (d, J=9.6 Hz, 2H), 8.374 (s, 1H), 13.030 (brs, 1H). LCMS (ES+) m/z: 299.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[Sn](CCCC)(CCCC)CCCC>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.O1CCOCC1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-c2nccn2C)cc1
Temperature: 100 °C

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.22 g), 1-methyl-2-tributylstannanyl-1H-imidazole (0.50 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and 1,4-dioxane (4.4 mL) was heated at 100° C. for 1 hour. The mixture was cooled to room temperature and used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:28][CH3:29])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine from Example 8 (199 mg, 0.984 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (219 mg, 1.08 mmol), HOAt (147 mg, 1.08 mmol), 4-methylmorpholine (0.238 mL, 2.16 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting residue was dissolved in AcOH (10 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated in vacuo and the residue was partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)propylcarbamate as a beige solid (234 mg, 64%). LCMS: RT 3.82 min [M+H]+ 370.5