Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]=[CH:7][N:6]([C@H:13]([CH3:30])[C@:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])([OH:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:5]2=[O:31].[NH4+:32].[OH-]>>[NH2:32][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:31])[N:6]([C@H:13]([CH3:30])[C@:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])([OH:21])[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:7]=[N:8]2)=[CH:3][C:2]=1[F:1]
Reactant: [NH4+]
Reactant: C[C@@H](n1cnc2cc(F)c(F)cc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [OH-]
Product: C[C@@H](n1cnc2cc(N)c(F)cc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Following a similar procedure to that described in example 40 but using (1R,2R)-6,7-difluoro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (obtained in example 15) and NH4OH the title compound was obtained as a white solid: mp 124°-125° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.45 (s, 1H, N=CH--N), 7.86 (d, J=11, 1H, arom), 7.76 (s, 1H, triazole), 7.72 (s, 1H, triazole), 7.6-7.4 (m, 1H, arom), 6.97 (d, J=8.0, 1H, arom), 6.9-6.7 (m, 2H, arom), 5.89 (dq, Jd =1.7, Jq =7.3, 1H, MeCH), 5.46 (d, J=1.7, 1H, OH), 5.15 (d, J=14.2, 1H, CH(H)), 4.43 (broad s, 2H, NH2), 4.01 (d, J=14.2, 1H, CH(H)), 1.26 (d, J=7.3, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 207 (N-ethylheterocycle, C10H10FN3O); [α]D =-0.31° (c 1, MeOH). Analysis calculated for C20H17 F3N6O2.H2O: C 53.57; H 4.27; N 18.74. Found: C 54.16; H 4.29; N 17.42.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O>CO>[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1/[CH:46]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1
Reactant: CSc1ccccc1C=O
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CSc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.10 g, 0.21 mmol) in methanol (0.60 mL) was added with DBU (0.047 mL, 0.32 mmol) and 2-methylsulfanylbenzaldehyde (0.035 g, 0.23 mmol) obtained in Step 2 was further added, followed by stirring at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was washed with hydrogen chloride-ethyl acetate solution and the precipitated solid was filtered. Then the solid was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to separate the mixture into organic layer and aqueous layer. The organic layer was concentrated under reduced pressure and the residue was washed with ethyl acetate/hexane (2/1, 1.0 mL) to obtain Compound 146 (0.016 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>CN(C=O)C>[CH3:28][O:26][C:25]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=1)=[O:27]
Reactant: CI
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The solution of 0.2 g (0.54 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester in 2 ml DMF was cooled down to 0° C. and 26 mg (0.54 mmol; 55% dispersion in mineral oil) were added. After 15 min., 38 μl (85 mg, 0.6 mmol) methyl iodide were added and the cooling bath was removed. After 5 hours the reaction mixture was poured on water and was extracted five times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.19 g (93%) the compound as a light yellow oil which was pure enough for the preceding steps without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH3:42][S:43]([O:1][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(COS(C)(=O)=O)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.122 g, 0.000278 mol) in methylene chloride (2 mL, 0.04 mol) was added triethylamine (0.0775 mL, 0.000556 mol) followed by methanesulfonyl chloride (0.0478 g, 0.000417 mol) at 0° C. The reaction was stirred at rt overnight, quenched with water, extracted with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate, then evaporated to dryness. The crude mixture was used directly in next step (138 mg, 96.02%). LCMS calculated for C23H33N6O4SSi(M+H)+: 517.2; Found: 517.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[N+:11]([O-:13])=[O:12])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile (7.12 g, 29.55 mmol) and morpholine (3.09 g, 35.45 mmol) in CH2Cl2 (98 mL) was added triethylamine (8.97 g, 88.64 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (40 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-(morpholinomethyl)-3-nitrobenzonitrile (5.84 g, 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.83 (br s, 2H), 3.84 (s, 2H), 3.67 (t, 4H, J=4.6 Hz), 2.45 (t, 4H, J=4.6 Hz).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:13](=[C:19]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:14](OCC)=[O:15])[CH3:12].Cl>C(Cl)Cl>[CH2:11]([C:13](=[C:19]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:14][OH:15])[CH3:12]
Reactant: CCOC(=O)C(CC)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CCC(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
Diisobutylaluminum hydride (79 mL of 1M solution, 79 mmol) was added to a solution of ethyl 2-ethyl-3,3-bis(4-fluorophenyl)propenoate (8.3 g, 26.3 mmol) in 150 mL of methylene chloride at -70° C. After stirring for 3 hours, the mixture was hydrolyzed by adding 2N hydrochloric acid. The aqueous fraction was separated and extracted with methylene chloride. The combined organic fractions were dried with magnesium sulfate and concentrated in vacuo to give 7 g of the title compound as an oil; MS(CI): m/e =274 for M+ of C17H16F2O.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][OH:16])C1C=CC=CC=1>C(O)C.[Pd]>[C:21]([O:20][C:18](=[O:19])[NH:17][C@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][NH2:10])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCN

Procedure:
Preparation takes place in analogy to Example 81A from 0.232 g (0.66 mmol) of benzyl{(4S)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl}carbamate (Example 246A) in 50 ml of ethanol with the addition of 23 mg of palladium on activated carbon (10%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:14][CH:13]=1.Cl.[C:34]([O:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])([CH3:37])([CH3:36])[CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:43][CH:42]([CH3:44])[C@H:40]([NH:41][C:27]([C:26]1[C:21]2[N:22]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:10]([NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:31])([F:1])[F:32])=[O:30])=[CH:17][CH:16]=3)=[N:19][N:20]=2)[N:23]=[CH:24][CH:25]=1)=[O:28])[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:45]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Nc1ccc(-c2nnc3c(C(=O)O)ccnn23)cc1)Nc1ccccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1ccnn2c(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)nnc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 3-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (66H) (38 mg, 0.086 mmol) in anhydrous DMF (1 mL) was added L-valine tert-butyl ester hydrochloride (23.4 mg, 0.11 mmol), EDC (24.7 mg, 0.13 mmol), HOBt (17 mg, 0.13 mmol), followed by DIPEA (45 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 3 h. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was partitioned between EtOAc and water, then the separated EtOAc layer was washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl, dried (anhydrous Na2SO4), and concentrated. The obtained crude residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-100%) in hexanes to afford 33 mg (63%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=4.04 min, [M+H]+=598.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:15]([O:17][C:18](=[O:28])[C@H:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH2:20])[CH3:16].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CO>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:20][C@H:19]([C:18]([O:17][CH2:15][CH3:16])=[O:28])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:6])=[C:2]([Cl:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1Cl)C(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (10.0 g, 49.6 mmoles), (L)-glutamate diethyl ester hydrochloride (11.9 g, 49.6 mmoles), and 1-hydroxybenzotriazole (6.7 g, 49.6 mmoles) in dry dimethylformamide (2150 mL) was stirred under nitrogen while triethylamine (5.02 g, 6.92 mL, 49.6 mmoles) was added dropwise during 1 minute. After 15 minutes, 1,3-dicyclohexylcarbodiimide (11.3 g, 54.6 mmoles) was added in portions during 1 minute. The reaction mixture was filtered after 18 hours and the solids were rinsed with dichloromethane (2×50 mL). The filtrate was spin evaporated (high vacuum) to an amber residue that was dissolved in dichloromethane (300 mL). The organic phase was washed successively with saturated bicarbonate, 5% citric acid, and brine solution (1×300 mL each). The organic phase was then dried (MgSO4), filtered, and poured onto a silica gel column (500 g, pre-wet with dichloromethane). The column was rinsed with dichloromethane (500 mL), followed by gradient elution of the product with 10% and 15% added ethyl acetate (8×250 mL fractions each). Like fractions were combined by spin evaporation and dried to give a white solid; yield, 9.8 g (51%); mp 95°-96° C.; 1H-NMR (DMSO-d6) δ 1.17 and 1.21 (2t overlapped, 6H), 1.8-2.2 (m, 2H), 2.46 (t obscured by DMSO, 2H), 4.0-4.2 (2 q overlapped, 4H), 4.46 (m, 1H), 7.68 (d, Jo =8 Hz, 1H), 8.25 (dxd, Jo =8 Hz, Jm =2 Hz, 1H), 8.34 (d, Jm 2 Hz, 1H), 9.14 (d, 1H); uv (MeOH) 260 nm max (9930), 236 min (6180), 205 max (25600); mass spec (CI) m/e 387 (100%), 341 (40), 184 (21).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=432.1, tR (minutes, Method F)=2.6. [α]D20=+37.86 (c=4.20 mg/mL,CHCl3)
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1.Cl>[Cu].N1C2C(=CC=CC=2)C=CC=1>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: COc1cc2cc(C(=O)O)sc2cc1O
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: COc1cc2ccsc2cc1O
Temperature: 0 °C

Procedure:
A mixture of the product from Step C (8 g), copper dust (2 g) and quinoline (40 mL) was heated under reflux for two hours. The hot reaction mixture was poured onto crushed ice (200 g), acidified with 6N hydrochloric acid and filtered. The filtrate was washed with saturated sodium chloride solution, dried (Na2SO4) and filtered and the solvent was evaporated in vacuo, leaving 5 g of waxy solid.
Reaction SMILES: [F:1][C:2]1[N:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=3[F:21])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:22][C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24].[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]([C:42](O)=[O:43])[C:36]2=[O:45])=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>C(O)C.O.C(OCC)(=O)C.[Cl-].[NH4+].CN(C)C=O>[CH:25]1([C:23]([NH:22][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][C:15]([NH:18][C:42]([C:37]5[C:36](=[O:45])[N:35]([C:32]6[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=6)[C:40]([CH3:41])=[CH:39][CH:38]=5)=[O:43])=[CH:14][C:13]=4[F:21])=[CH:7][N:6]3[C:2]=2[F:1])=[O:24])[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn2c1F)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)c(F)n4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
A mixed solution of N-[3-fluoro-6-(2-fluoro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (15.2 mg, 0.041 mmol), reduced iron (12.1 mg, 0.205 mmol) and ammonium chloride (21.9 mg, 0.41 mmol) in ethanol (1 mL) and water (0.2 mL) was stirred at 90° C. for 5 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue and 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (12.2 mg, 0.0492 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (14 μL, 0.082 mmol) and HATU (18.7 mg, 0.0492 mmol), and the mixture was stirred at room temperature for 17 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1→ethyl acetate alone) to give a white solid. The obtained solid was washed with ethyl acetate and collected by filtration to give the title compound (8 mg, 34%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:24][C:10]1[N:9]([CH2:8][C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Synthesized as described in Example 310D using 1-[(3-bromophenyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 318A) and [4-(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 459 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([NH:9][NH2:10])[CH:8]=1.C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>CO>[NH2:20][C:19]1[N:9]([C:7]2[CH:8]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[CH3:11])[N:10]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: Cc1ccc(Br)cc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CO
Product: Cc1ccc(Br)cc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
5 (5-Bromo-2-methylphenyl)hydrazine hydrochloride (CAS no. 214915-80-7) (5 g, 21.05 mmol) was partitioned between EtOAc (50 mL) and NaOH (2M, aq) (30 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to afford free base of the starting material. The resultant oil was suspended in MeOH (50 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (2.57 g, 21.05 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (5.48 g, 94%). 1H NMR (400 MHz, DMSO) 1.99 (3H, s), 6.59 (2H, s), 7.36 (1H, d), 7.49 (1H, d), 7.60-7.63 (1H, m), 7.76 (1H, s); m/z (ES+) (M+H)+=277+279; HPLC tR=2.01 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]([F:71])([F:70])[C:61]1[CH:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[CH:66][C:61]([C:60]([F:71])([F:70])[F:59])=[CH:62][CH:63]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(C(F)(F)F)cc2)=C3c2cc(F)cc(F)c2)CC1
Yield: 69 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:14]2[C:13]([CH3:23])=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Fc1ccc(C2CCCN2)cc1
Product: Cc1ccccc1S(=O)(=O)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, colorless oil, MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-2-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C:13](=[O:36])[C@H:14]([NH:28]C(=O)OC(C)(C)C)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CC(O)=O>CS(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:28][C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13]([NH2:12])=[O:36])[CH:9]=1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccncc2)cc1)C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N[C@H](Cc2ccc(-c3ccncc3)cc2)C(N)=O)cc1Br
Yield: 47.2 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (85 mg, 0.390 mmol), (R)-tert-butyl 1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylcarbamate (72 mg, 0.299 mmol) and DIEA (0.200 mL, 1.15 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (62 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][C:17]([O:19]CC)=O)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[NH:11]3)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>CO>[CH3:26][NH:27][C:17](=[O:19])[CH2:16][C:15]1[N:14]2[C:10]([NH:11][C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=32)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CN
Reactant: CCOC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Solvent: CO
Product: CNC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of ethyl 2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetate in 60 ml of methanol are treated with 60 ml of liquid methylamine, while stirring the mixture at room temperature for 16 h. The solvent is evaporated under reduced pressure. The residue is washed with water and recrystallized twice from N,N-dimethylformamide. 0.8 g of compound is finally isolated. Melting point: 303°-308° C. (decomposition).