Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 80.4 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)(methyl)carbamate (442 mg, 1.45 mmol) to afford the desired product (446 mg, 80%) as an orange-red solid. ESI MS m/z 554 [C27H32BrN5O3+H]+
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.[C:23](I)([F:26])([F:25])[F:24].OO>CS(C)=O>[CH3:1][N:2]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:5]2[CH2:4][CH2:3]1
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: FC(F)(F)I
Agent: OO
Solvent: CS(C)=O
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Yield: 63.9 %

Procedure:
To tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (10.0 g, 32.7 mmol) in DMSO (164 mL) was added ferrous sulfate heptahydrate (9.8 mL of 1.0 M, 9.8 mmol) followed by CF3I (6.41 g, 32.7 mmol) by slow bubbling through the solution and taking the weight difference of the canister. The mixture was cooled with a ice-water bath before H2O2 (3.71 mL of 30% w/v, 32.7 mmol) dropwise over 15 min keeping the internal temperature<20° C. The mixture was poured onto 300 mL of ice water and was extracted with EtOAc (2×400 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified column chromatography eluting with 0-10% methanol in dichloromethane with 2% iPr2NEt to give tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (7.8 g, 64%).
Reaction SMILES: BrC1C=CC=CC=1OC1C=CC=CC=1Br.C([C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])(C)(C)C.[CH3:28][C:29]([CH3:32])([O-:31])[CH3:30].[Na+].[Br-]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:31][C:29]([CH3:32])([CH3:30])[CH3:28])=[O:21]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)C(=O)N1CCNCC1
Agent: Brc1ccccc1Oc1ccccc1Br
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Part B: To a solution of the bromophenyl ether of Part A (10.0 g, 41.1 mmol) in toluene (80 mL) was added 1-tert-butylcarbonylpiperazine (Lancaster, 9.2 g, 49.4 mmol) and sodium tert-butoxide (Fluka, 5.5 g, 57.5 mmol). The reaction stirred at ambient temperature for twenty minutes. BINAP (Aldrich, 0.8 g, 1.2 mmol) and tris(dibenzylideacetone)dipalladium (0) (Aldrich, 0.4 g, 0.4 mmol) were then added and the reaction was stirred at 80° C. until the bromide was exhausted. Work up comprised cooling the mixture to ambient temperature, filtering through a Celite® pad, and concentrating the filtrate. The resulting residue was purified on silica gel (ethyl acetate/hexanes) to afford the BOC-piperazine as a black oil (6.4 g, 44% yield). 1H NMR showed the desired compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:32]3[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[NH:35][CH2:34][CH2:33]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: OCC1CCNCCN1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC(CO)CC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and the product of step i).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-aminoindan (15.0 g, 0.1128 mol) and triethylamine (11.92 g, 0.1184 mol) in 200 ml ethanol was added dropwise ethyl bromoacetate (18.83 g, 0.1128 mol). After the addition was complete the mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was dissolved in ether, washed with H2O (4×300 ml), brine and dried (MgSO4). Concentration of the volatiles in vacuo provided a crystalline material which was recrystallized from petroleum ether; b.p. 30°-60° C., m.p. 49° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[N:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]2=[N:9][CH:8]=1.C([Sn](Cl)(CCCC)CCCC)CCC.Cl[C:35]1[S:39][N:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1>C1COCC1.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.[Cu]I>[S:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:37]1[N:36]=[C:35]([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]3=[N:9][CH:8]=2)[S:39][N:38]=1
Reactant: Clc1nc(-c2cccs2)ns1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccn2c(-c3nc(-c4cccs4)ns3)cnc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
A solution of iPrMgCl (2.0M in THF, 1.13 ml, 2.26 mmol) was added dropwise to a stirred suspension of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (547 mg, 2.06 mmol) in THF (20 ml) at −78° C. under N2. The resulting solution was stirred at −78° C. for 15 min and then tributyltin chloride (670 μl, 2.47 mmol) was added. The reaction was warmed to 0° C. and stirred for 1 h. 5-Chloro-3-(thien-2-yl)-[1,2,4]thiadiazole (500 mg, 2.47 mmol) and tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.21 mmol) were added and the reaction heated at reflux for 1 h. Copper(I) iodide (50 mg, 0.26 mmol) was added and heating continued for a further 1.5 h. The mixture was concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica, using 50% EtOAc in hexane as the eluent, and subsequent recystallisation from dichloromethane/isohexanes gave 3-[3-(thien-2-yl)-[1,2,4]thiadiazol-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (188 mg, 26%): δH (400 MHz, d6-DMSO) 7.30 (1H, t, J 3.7), 7.83-7.90 (2H, m), 8.11 (1H, dd, J 3.7 and 1.1), 9.14 (1H, s), 10.20 (1H, d, J 7.1); m/z (ES+) 353 (M+).
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O:11]CC=C)=[O:10])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:50].C(OCC)(=O)C>C(OCC)C.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(Cl)Cl.C(OCC)(=O)C>[N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10])=[N+:2]=[N-:3].[K+:50]
Reactant: C=CCOC(=O)C1=C(N=[N+]=[N-])C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N=[N+]=[N-])C[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of allyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (42 mg, 0.15 mmol) and triphenylphosphine (12 mg, 0.045 mmol) in 1:1 methylene chloride-ethyl acetate (2.7 ml) is treated with 0.5M potassium 2-ethylhexanoate in ethyl acetate (0.3 ml, 0.15 mmol) and tetrakis(triphenylphosphine)palladium (0) (13.8 mg, 0.012 mmol). The mixture is stirred 15 minutes at ambient temperature under a nitrogen atmosphere, diluted with diethyl ether, and centrifuged. The insoluble pellet is washed with ether and dried under vacuum to afford potassium (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3C(F)(F)F)cc2)c1C
Yield: 13.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.25 g, 0.67 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.033 mmol), crude 1-bromo-4-(2-(trifluoromethyl)phenylsulfanyl)-benzene (0.27 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-phenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.045 g, 16%) as a solid.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[S:24][C:25]([C:28]([OH:30])=O)=[CH:26][N:27]=1)=[O:21].[CH2:31]1[C:39]2[C:34](=[CH:35]C=CC=2)[CH2:33][N:32]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:33][CH:34]([CH3:35])[CH2:39][CH2:31][NH:32][C:28]([C:25]1[S:24][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:27][CH:26]=1)=[O:30]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1cnc(NC(=O)N2Cc3ccccc3C2)s1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)N2Cc3ccccc3C2)s1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 2-(isoindoline-2-carboxamido)thiazole-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.01-11.16 (bs, 1H), 8.27 (t, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.29-7.36 (m, 4H), 4.73-4.88 (bs, 4H), 3.18-3.28 (m, 2H), 1.52-1.69 (m, 1H), 1.34-1.44 (m, 2H), 0.90 (d, J=6.6 Hz, 6H); MS (ESI(−)) m/e 357 (M−H)−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:2]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=Cc1csc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: c1ccc(N2CCN(Cc3csc4ccccc34)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Benzothiophene-3-carbaldehyde (6.17 mmole), 1-(2-pyridinyl)piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2-dichloroethane and stirred at 0° C. for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether:dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography with 96:4:0.5 dichloromethane/methanol/saturated aqueous ammonia to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.62 (t, 4H, J=4.5 Hz), 3.51 (t, 4H, J=4.5 Hz), 3.82 (s, 2H), 6.65 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 7.40 (m, 2H), 7.48 (s, 1H), 7.53 (m, 1H), 7.86 (m, 1H), 8.04 (m, 2H); MS (DCI/NH3) m/z 310.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@H:31]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:32][OH:33]>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=[C:2]([NH:30][C@H:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:32][OH:33])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Cc1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-nitropyrimidin-4-amine (Method 75; 1.0 g, 3.4 mmol), DIEA (0.57 g, 4.4 mmol), and (R)-2-amino-2-(4-fluorophenyl)ethanol (0.58 g, 3.7 mmol) in n-BuOH (15 ml) was heated to 60° C. for 2 hours. The reaction was then cooled to 25° C., concentrated, and treated with hexane. The resulting solid was collected by filtration to give the title compound (1.3 g, 93%). MS: Calcd.: 413; Found: [M+H]+ 414.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.F[B-](F)(F)F.[Li+].[O:15]1[CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][CH2:16][OH:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C1COC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC#N
Product: OCCCNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 67.9 %

Procedure:
4-Chloroaniline (4.39 g) and lithium tetrafluoroborate (3.32 g) were added to a solution of oxetane (1.00 g) in acetonitrile (20 mL) at room temperature, and the reaction solution was stirred at room temperature for 52 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.17 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([C@H:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 h. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:6]#[N:7].[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][C:27]([CH3:31])=[N:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[O:2][CH3:1])=[N:26][C:27]([CH3:31])=[N:28]2)=[CH:23][CH:22]=1
Reactant: COc1cc(C#N)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(Cl)c2ccc(Br)cc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1-c1nc(C)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.072 g, 0.088 mmol), 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate GGGG) (0.500 g, 1.930 mmol), 7-bromo-4-chloro-2-methylquinazoline (0.452 g, 1.754 mmol), and potassium carbonate (0.970 g, 7.02 mmol) in 3 mL dioxane was treated with 1 mL water and was allowed to stir at room temperature 3 hours. LC/MS showed mostly product, so the reaction mixture was diluted with DCM and washed with water. The aqueous layer was removed and the reaction mixture was concentrated. The crude residue was carried forward to step 2 without purification. (M+H)+=354.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:14]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=12.I[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:14]=2)=[C:6]2[CH2:11][CH2:10][N:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8](=[O:12])[C:7]=12
Reactant: Ic1ccccc1
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)NCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(c1ccccc1)CC2
Temperature: 150 °C

Procedure:
To a solution of 3-(methylsulfanyl)-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (Example 3) (20 mg, 0.051 mmol) in DMF (120 μL) at rt was added iodobenzene (21 mg, 0.101 mmol), K2CO3 (7 mg, 0.051 mmol) and CuI (1.0 mg, 0.0051 mmol). The reaction mixture was heated at 150° C. for 72 h. The resulting mixture was concentrated and purified directly by silica gel chromatography (gradient elution, 0-50% EtOAc/hexanes) to afford the title compound. LRMS (ESI) m/z 471.9 [(M+H)+; calcd for C23H29N3O2S2Si: 472].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:42](=[O:44])[CH:41]([C:31]2[CH:32]=[CH:33][C:34]([N:35]3[C:39]([CH3:40])=[N:38][N:37]=[N:36]3)=[C:29]([Cl:28])[CH:30]=2)[CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)=[N:53][CH:54]=1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (prepared in Example 3, 151 mg, 0.45 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (234 mg, 1.35 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionamide (90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd for C21H22BrClN6O (M+) 489.0727, found 489.0727.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]=2[Cl:14])[NH:7][CH:6]=1)C.[C-:19]#[N:20].[K+].CI>CN(C=O)C>[C:19]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]=2[Cl:14])[NH:7][CH:6]=1)#[N:20]
Reactant: CCCOc1ccc2[nH]cc(CN(C)C)c2c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCOc1ccc2[nH]cc(CC#N)c2c1Cl

Procedure:
Reaction of 3-dimethylaminomethyl-4-chloro-5-n-propyloxyindole (3.50 g, 13.1 mmol) with potassium cyanide (3.28 g, 50.4 mmol) and methyl iodide (7.44 g, 52.4 mmol) in DMF by the method described in 1 (d) gave 3-cyanomethyl-4-chloro-5-n-propyloxyindole as an oil which crystallised on standing (2.53 g).