Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:21]([C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])[OH:22])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet was added 150 ml of anhydrous diethyl ether and 94 ml of 1.6 molar butyllithium solution (in hexane). The system was cooled to -120° C. and 14.5 ml of 3-bromopyridine in 75 ml of tetrahydrofuran was added over 1 hour. After addition of the 3-bromopyridine, the system was stirred for an additional 45 minutes. At this time, 26.25 gm of 2,4-dichlorobenzaldehyde in 75 ml of tetrahydrofuran was added to the system while still maintaining at temperatures of -120° C. The system was kept at -120° C. for an additional 6 hours after addition of the 2,4-dichlorobenzaldehyde and afterwards allowed to come to room temperature. After 10 hours at room temperature, the system was quenched with saturated ammonium chloride (in water). The system was then adjusted to a pH 2 with concentrated HCl solution. The solution was extracted with diethyl ether. The aqueous solution was made basic with a 50% NaOH solution. The product was extracted with methylene chloride and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 25.75 gm of the 3-pyridyl-2,4-dichlorophenyl-carbinol as tan solid, m.p. 108°-111° C., and listed as compound number 2 in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1cc2ccccc2o1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-bromoacetylbenzo[b]furan (960 mg) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 50 min the reaction mixture was cooled to 3° C. and the solid collected. The filtrate was evaporated and the residue was subjected to preparative thin-layer chromatography developing with chloroform-ethanol (50:1) (4 runs) which gave a yellow solid. The two solids were combined and crystallised twice from acetone to give the title pyrimidinone (415 mg) m.p. 202°-205° C., λmax (EtOH) 227.5 nm (ε14,060), 298 nm (ε20,930).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CC[C@H]1c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To an ice cold solution of commercially available (2R,5S)-5-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 3.45 mmol) in 1,2-dimethoxyethane (5 mL) is added 4-methylmorpholine (0.4 mL, 3.795 mmol) and isobutyl chloroformate (0.50 mL, 3.795 mmol). Stir 15 min and filter into cold flask. Add sodium borohydride (0.196 g, 5.17 mmol) in water (3 mL), followed by addition of water (50 mL). Extract product with ethyl acetate (3×50 mL) and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and purify on silica gel to give the title compound (0.886 g, 93%).
Reaction SMILES: NC1C(C(F)(F)F)=CC(/C=C(\CC([O-])=O)/C(OC)=[O:15])=CC=1Br.NC1C(C(F)(F)F)=CC(C[C@@H](CC(=O)N2CCC(N3CCC4C=CC=CC=4NC3=O)CC2)C(O)=O)=CC=1Br.[NH2:61][C:62]1[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][C:65]([CH2:66][C@@H](CC([O-])=O)C(OC)=O)=[CH:64][C:63]=1[Cl:82].NC1C(C(F)(F)F)=CC(C[C@@H](CC(=O)N2CCC(N3CCC4C=CC=CC=4NC3=O)CC2)C(O)=O)=CC=1Cl>>[NH2:61][C:62]1[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][C:65]([CH:66]=[O:15])=[CH:64][C:63]=1[Cl:82]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: COC(=O)/C(=C/c1cc(Br)c(N)c(C(F)(F)F)c1)CC(=O)[O-]
Agent: Nc1c(Br)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C=O)cc1C(F)(F)F

Procedure:
Analogously to the sequence described in 9f to 9i, 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid were able to be obtained from 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde (see Example 1b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][CH:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[CH:47]=2)[CH:10]=[C:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=CC(COc2cccc(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 42, 500 mg, 1.66 mmol), triphenylphosphine (653 mg, 2.49 mmol) and 3-fluorophenol (0.23 ml, 2.49 mmol) in tetrahydrofuran (30 ml) at 0° C. under a nitrogen atmosphere was added diisopropylazodicarboxylate (0.49 ml, 2.49 mmol) dropwise over 5 minutes and stirred to room temperature over 72 hours. Solvent was removed under reduced pressure and the residue purified by chromatography on silica gel, eluting with 10-15% ethyl acetate/heptane to give the title compound as a mixture of diastereomers (˜5:1 2S,4S:2S,4R) as a colourless oil (370 mg, 51%)
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:18][C:17]3=[O:37])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:18][C:17]3=[O:37])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C1NC(c2ccccc2)(c2ccc([N+](=O)[O-])cc2)C(=O)N1CCCN1CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C2(c3ccccc3)NC(=O)N(CCCN3CCC(c4ccccc4)CC3)C2=O)cc1

Procedure:
3-[3-(4-phenyl-1-piperidyl) propyl]-5-(4-nitrophenyl)-5-phenylhydantoin (17.5 g, 0.035 mole) in 200 ml of glacial acetic acid and 0.6 g of Pd/C (10%) was reduced on the Parr shaker. The theoretical amount of hydrogen was taken up. The mixture was filtered and concentrated. The concentrate in aqueous methanol was made basic with NH4OH. The solid was recrystallized from aqueous dimethylformamide-methanol and twice from aqueous dioxane.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]2)=[CH:57][C:56]=1[O:71][CH3:72]>CN(C)C=O>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([CH:61]4[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]4)=[CH:57][C:56]=3[O:71][CH3:72])=[N:3]2)=[C:8]([CH3:23])[CH:9]=1)(=[O:20])=[O:19]
Reactant: Cc1cc(-c2ccccc2N(C)S(C)(=O)=O)n2nc(O)ncc12
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8-dram vial, N-[2-(2-Hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (87 mg, 0.26 mmol), N,N-Dimethylformamide (0.948 mL), N,N-Diisopropylethylamine (0.100 mL, 0.576 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.112 g, 0.314 mmol) were added. The reaction was stirred at room temperature for 30 minutes. 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.152 g, 0.576 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidin-1-yl]-acetamide as a yellow solid. LCMS (E/I+) 578.16 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.93-7.98 (m, 1H), 7.88 (d, 1H, J=8.18 Hz), 7.61-7.67 (m, 1H), 7.57 (s, 1H), 7.51-7.56 (m, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 6.68 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.05 (s, 3H), 2.85-2.95 (m, 7H), 2.35-2.45 (m, 4H), 2.08-2.28 (m, 2H), 1.64-1.81 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][O:19][CH2:20][C:21](OC)=[O:22])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.CO.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:21](=[O:22])[CH2:20][O:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:25])([F:26])[F:1])=[N:4][N:5]=3)[N:8]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 48.8 %

Procedure:
A stirred solution of methyl 2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetate (95 mg, 0.25 mmol) in 2M dimethylamine in methanol (2.0 mL, 4.00 mmol) was heated at 120° C. in a microwave reactor for 1 hour. The reaction mixture was evaporated and the crude product was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N,N-dimethyl-2-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetamide (48.0 mg, 48.8%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNC(CO)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and serinol (0.1 mL, 1.09 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (14.2 mg, 28.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O5S+H [(M+H)+]: 751.2948. found: 751.2943.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:17])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2>C(Cl)Cl>[OH:6][C:7]1[C:8]([CH3:17])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1C)CCC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(O)ccc2c1CCC2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Add dropwise a solution of BBr3 (14.8 g, 59.1 mmol) dissolved in DCM (50 ml) to a solution of 5-Methoxy-4-methyl-1-indanone (Tetrahedron (1970), 26(11), 2599-608) (4.17 g, 23.6 mmol) dissolved in DCM (50 ml) and cooled to −78° C. under nitrogen. After stirring at −78° C. for one hour, remove the cold bath and stir at ambient temperature overnight. Cool the reaction mixture to −78° C. and quench with saturated aqueous NaHCO3. Dilute mixture with water and extract with EtOAc (2×). Wash extracts with water and brine, dry (MgSO4) and concentrate on rotary evaporator to give 5-hydroxy-4-methyl-1-indanone (2.60 g) as an amber solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=2[N+:27]([O-:29])=[O:28])=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.32 g, 3.2 mmol) and ethyl isocyanate (0.23 g, 3.2 mmol) were added to a solution of 3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole (0.69 g, 2.9 mmol) in ethyl acetate (10 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow solid of N-ethyl-3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (0.72 g, yield: 79.7%). mp: 81-84° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.34 (dq, J=1.4 and 7.2 Hz, 2H), 5.78 (q, J=0.8 Hz, 1H), 6.71 (br s, 1H), 7.34-7.37 (m, 2H), 7.73 (ddd, J=1.2, 2.2 and 7.7 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Agent: Br
Product: O=C(O)C1CCc2cc(O)ccc21

Procedure:
In a 20-liter reactor provided with a mechanical stirrer, 1.6 kg of 2,3-dihydro-5-methoxy-1H-inden-1-carboxylic acid and 8 l of 48% hydrobromic acid were introduced and heated at 135°-140° C. in oil bath for 15 hours. The mixture was allowed to cool, and the hydrobromic acid was evaporated at vacuum; to the blackish residue, 3 l of toluene were added and the solvent was evaporated at vacuum. This operation was made again with further 3 l of toluebe to give the desired compound as blackish solid, 1.5 kg (100%), m.p. 137°-138° C. and acid group titration: 101%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[C:7]([CH3:16])[CH:6]=[CH:5]2.[Se](=O)=[O:18]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:16]=[O:18])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 35 %

Procedure:
To 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 5.02 mmol) in dioxane/water (3.5 ml/0.3 mL) at ambient temperature was added selenium dioxide (0.668 g, 6.02 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-8-isopropoxyquinoline-2-carbaldehyde (410 mg, 35.0% yield) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[S:23][C:24]([C:28]([OH:31])([CH3:30])[CH3:29])=[C:25]([CH3:27])[N:26]=3)[S:21][C:14]=12>>[CH3:27][C:25]1[N:26]=[C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:19]=2)[S:23][C:24]=1[C:28]([OH:31])([CH3:30])[CH3:29]
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(C)(C)O
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nc(C)c(C(C)(C)O)s5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 2-[2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-propan-2-ol by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.07 (t, 1H), 7.62 (d, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.58 (t, 1H), 6.10 (d, 1H), 5.46 (d, 1H), 2.46 (s, 3H), 2.40 (s, 3H), 1.60 (s, 6H); RP18-HPLC RT: 5.17 minutes; API MS: 435 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=[O:7].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOC(C)=O>[Cl:16][CH2:17][C:18]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19]
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NNC(=O)CCl)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To 3-(methyloxy)-4-nitrobenzohydrazide (3.65 g, 17.3 mmol) in EtOAc (150 mL) was added chloroacetyl chloride (1.50 mL, 18.8 mmol). The reaction was stirred open to air overnight. The solid was filtered and washed with diethyl ether to provide the title compound (3.17 g, 11.0 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.98 (s, 3H), 4.21 (s, 2H), 7.56 (dd, J=8.2, 1.6 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 10.48-10.54 (m, 1H), 10.82 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Yield: 80.6 %

Procedure:
A solution of 4-chloro-2-fluoro-5-nitroaniline (5.0 g, 26.3 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (5.73 g, 27.6 mmnol) in acetic acid is refluxed for 4 hours and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a beige solid (7.5 g, 81% yield, mp 230-232° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccncc1
Yield: 12 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and H, alkylating with 4-chloromethylpyridine, in 12% yield and isolated as a beige solid, mp 153°-154° C.; IR (KBr) 3204, 1679, 1505, 1407, 1283, 1256, 1077, 1065, 750 cm-1 ; 1H NMR (CDCl3) δ2.18-2.38 (m, 3H), 3.93 (br q, J=3.9 Hz, 2H), 4.88 (dd, J=7.7, 5.4 Hz, 1H), 5.15 (s, 2H), 6.73 (d, J=7.6 Hz, 1H), 6.92 (td, J=6.7, 3.2 Hz, 1H), 6.98-7.06 (m, 2H), 7.15 (d, J=5.9 Hz, 2H), 8.56 (dd, J=4.5, 1.5 Hz, 2H); MH+ at m/z=285; Anal. Calc'd for C16 H16N2O3 : C, 67.59; H, 5.67; N, 9.85. Found: C, 67.67; H, 5.78; N, 9.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([CH2:17][OH:18])[CH2:16][CH2:15]2)=[N:11][C:10]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]2=[CH:21][CH:20]=1.[CH3:35][S:36](O)(=[O:38])=[O:37]>ClCCl.CO.CO>[CH3:35][S:36]([O:18][CH2:17][C:14]1([C:12]2[NH:13][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:10]([C:19]3[N:24]=[C:23]4[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]4=[CH:21][CH:20]=3)[N:11]=2)[CH2:15][CH2:16]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)O
Reactant: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(CO)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Solvent: CO
Solvent: ClCCl
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(COS(C)(=O)=O)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
[1-[5-(2,4-Difluorophenyl)-4-[2-[[(1S)-2-ethoxy-1-methyl-ethyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]cyclopropyl]methanol (0.56 g, 1.19 mmol) is dissolved in a 1:1 mixture of dichloromethane/methanol (12 mL total). A 0.5 M solution of methanesulfonic acid in methanol (2.37 mL) is added dropwise to the solution. The mixture is stirred at RT for 30 min and then the solvent is evaporated under reduced pressure. The residue is mixed with methanol and concentrated twice to afford the title compound (0.64 g, 96%). LC-ES/MS m/z 470.1 (M+1).