Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH:20]([CH3:22])[CH3:21])=[N:8][CH:9]=[N:10][CH:11]=1)=O)C.[OH-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>O1CCOCC1>[CH:20]([N:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[C:4]1=[O:3])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cncnc1Nc1ccccc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)N1C(=O)c2cncnc2Nc2ccccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
12.7 g (0.03 mol) of 5-ethoxycarbonyl-4-(2-isopropylaminoanilino)pyrimidine in 42.2 ml of a 0.1 N. aqueous sodium hydroxide solution are heated for 1 hour under reflux. The solvent is removed on a rotary evaporator and the crystalline residue is dried in vacuo at 60° C. 28.9 g (0.11 mol) of triphenylphosphine and 16.9 g (0.11 mol) of carbon tetrachloride are added to the dry product, dissolved in 150 ml of absolute dioxan, and the mixture is stirred for 5 hours at 80° C. The solvent is removed on a rotary evaporator, and the oily residue which remains is chromatographed on neutral silica gel using 99:1 methylene chloride/methanol as the eluant; yield: 6.3 g, with m.p. 204° to 206° C. (from isopropanol).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1([CH2:8][O:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: NC1(CO)CCCCC1
Product: NC1(COC(c2ccccc2)c2ccccc2)CCCCC1

Procedure:
This was prepared as described in Preparation 1 using 1-aminocyclohexane-1-methanol and benzhydrol. The title compound was obtained as a pale yellow oil (2.02 g, 68%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[C:24]([O:26]CC2C=CC=CC=2)[C:23]([C:34]2[N:38]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:43][CH:44]=3)[C:37]([OH:51])=[N:36][N:35]=2)=[CH:22][C:21]=1[CH:52]([CH3:54])[CH3:53])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.[Pd]>[P:1]([OH:3])([OH:11])([O:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([C:34]2[N:38]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:43][CH:44]=3)[C:37]([OH:51])=[N:36][N:35]=2)=[CH:22][C:21]=1[CH:52]([CH3:54])[CH3:53])=[O:2]
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)nc2)c(OCc2ccccc2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)nc2)c(O)cc1OP(=O)(O)O
Yield: 77 %

Procedure:
Mixture (6) (2.3 g) was hydrogenated in MeOH (50 mL) using Pd/C (10%, dry, 200 mg) and H2 balloon at 1 atm at room temperature for 2 hr. Pd/C was filtered off through a pad of celite and the mother liquid was concentrated to give Compound 2 as white solid (1.13 g, 81%).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[O:3][C:4]1[CH:9]=CC[CH2:6][CH:5]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]#[C:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH:9]=[C:4]([O:3][Si:2]([CH3:11])([CH3:10])[CH3:1])[CH:5]=[CH:6][C:13]=1[C:12]([O:17][CH3:18])=[O:16]
Reactant: CC#CC(=O)OC
Reactant: C[Si](C)(C)OC1=CCCC=C1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(O[Si](C)(C)C)cc1C
Temperature: 150 °C
Yield: 67.1 %

Procedure:
A 50 mL round bottom flask equipped with magnetic stir bar and condenser was charged with 6.0 g of 2-trimethylsilyloxy-1,3-cyclohexadiene, 3.5 g methyl tetrolate in 3 mL dry toluene. The reaction was heated to 150° C. for 50 hours at which point 1H-NMR indicated no starting diene. The raction was concentrated in vacuo to provide 5.7 g (67%) methyl 2-methyl-4-trimethylsilyloxybenzoate.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][OH:16])([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(CO)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1 N NaOH (0.994 mL, 0.994 mmol) was added to a solution of ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (73.6 mg, 0.331 mmol) in THF (1 mL) and MeOH (1 mL) and the mixture was stirred at rt for 3-4 h. The reaction mixture was acidified and extracted with EtOAC, washed with brine and dried (MgSO4). Evaporation of the solvent afforded Cap-6 as a beige solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.74 (s, 2H), 2.30-2.20 (m, J=13.3 Hz, 2H), 2.13-1.85 (m, 4H), 1.71-1.60 (m, 2H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[O:9])[CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cccnc2)cc1
Yield: 85.1 %

Procedure:
A mixture of 1.83 g (0.01 mol) of nicotinoyl chloride hydrochloride (97%), 1.65 g of (0.01 mol) of ethyl 4-aminobenzoate, 2.22 g (0.022 mol) of triethylamine and 61 mg of 4-dimethylaminopyridine in 33 ml of dichloromethane is refluxed 24 hours. The solution is washed with water, 2N citric acid and NaHCO3 solution. The solvent is removed and the residue triturated with methanol to give 2.3 g of ethyl 4-[(3-pyridinylcarbonyl)amino]benzoate as yellow crystals, m.p. 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: COc1nnc(Cl)cc1C(C)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1nnc(Cl)cc1C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.85 g 1-(6-Chloro-3-methoxy-pyridazin-4-yl)-ethanol is dissolved in 300 ml tetrahydrofuran and 35.5 g of manganese dioxide is added. The reaction is stirred for 48 h at RT. Solids are removed by filtration, and the solvent is removed under reduced pressure. The product is purified and separated from 1-(3-chloro-6-methoxy-pyridazin-4-yl)-ethanone by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 2.4 g. LC-MS (ES+) 187 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:23])=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26](=[O:40])[C@@H:27]1[CH2:31][C@@H:30](O)[CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:23][C@@H:30]3[CH2:29][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:27]([C:26]([O:25][CH3:24])=[O:40])[CH2:31]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Reactant: COC(=O)[C@@H]1C[C@@H](O)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: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The 7-methoxy-8-methyl-2-(4-(trifluoromethyl)thiazol-2-yl)quinolin-4-ol BO (10.0 g, 1 eq.), the N-Boc-trans-4-hydroxyproline methyl ester BP (7.20 g, 1 eq.), and the triphenylphosphine (11.56 g, 1.5 eq.) in suspension in THF (250 mL) under N2 were cooled down to 0° C. The DIAD (8.70 mL, 1.5 eq.) was added dropwise. The reaction mixture was allowed to warm up and stir at room temperature for 1.25 hrs, then cooled again at 0° C. and additional 1 more eq. of DIAD was added. The reaction mixture was stirred for 2 hrs at room temperature, and then concentrated in vacuo to 50 mL. Water and ethyl acetate were added and the phases were separated. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound BQ (16.75 g, 87% purity). MS (ESI, EI+) m/z=568.3 (MH+); 626.5 (M+OAc−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:35]1[C:29]3[C:30](=[N:31][CH:32]=[C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH:28]=3)[C:33]3([CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:34]1)=[C:3]([CH3:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (58.1 mg, 0.20 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (55 mg, 0.20 mmol), XPhos pre-catalyst (14.8 mg, 0.02 mmol) and sodium tert butoxide (38.4 mg, 0.40 mmol) in toluene (4 mL) at 90° C. for 2 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dt, J=4.8, 1.4 Hz), 7.86-7.95 (2H, m), 7.70 (1H, ddd, J=9.3, 2.5, 1.5 Hz), 7.55-7.60 (1H, m), 7.39-7.46 (1H, m), 6.96-7.06 (1H, m), 5.70-5.85 (1H, m), 4.07-4.21 (2H, m), 3.87-4.01 (2H, m), 3.71-3.81 (4H, m), 3.50-3.63 (2H, m), 2.96-3.06 (4H, m), 2.19-2.44 (5H, m), 1.68-1.86 (2H, m). Mass Spectrum (ESI) m/e=530.0 (M+1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1.Br>C(OC(=O)C)C>[Br:1][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:10]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: Br
Solvent: CCOC(C)=O
Product: O=C1c2cc(Cl)ccc2CC1Br
Reaction time: 3 h

Procedure:
A solution of 9.59 g (60.0 mmoles) of bromine in 20 ml of acetic acid ethyl ester is added dropwise to a solution of 10.0 g (60.0 mmoles) of 6-chloro-1-indanone in 80 ml of acetic acid ethyl ester and 0.5 ml of 48% strength aqueous hydrobromic acid. After stirring for 3 hours, the reaction solution is concentrated to dryness, the residue is stirred with 50 ml of water and the precipitate is filtered off. The crude product of melting point 84°-87° is recrystallized from petroleum ether 60/70 and gives the pure product of melting point 92°-94° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-cyanophenol: 1H NMR (300 MHz, CD3OD) δ 7.74 (d, J=8.8 Hz, 1H), 7.61 (app. d, J=8.8 Hz, 2H), 7.37 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.9, 2.4 Hz, 1H), 7.02 (app. d, J=8.8 Hz, 2H), 4.43 (q, J=8.9 Hz, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.08 (t, J=5.1 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[CH:21]=[CH2:22])[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4]C=C>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[O:1]=[C:2]1[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[CH:21]=[CH:22][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC[C@@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC=C[C@H]2CCCCN2C1=O
Temperature: 60 °C
Yield: 71.9 %

Procedure:
A solution of tert-butyl (S)-1-oxo-1-((R)-2-vinylpiperidin-1-yl)pent-4-en-2-ylcarbamate (1.00 gm, 3.24 mmol) in DCE (350 mL) was purged with argon for 10 min. Grubbs II catalyst (0.124 gm, 0.146 mmol) was added and the reaction mixture was heated at 60° C. under argon for 18 hr. The reaction mixture was concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give tert-butyl (7S,10aR,Z)-6-oxo-1,2,3,4,6,7,8,10a-octahydropyrido[1,2-a]azepin-7-ylcarbamate (653 mg, 2.33 mmol, 71.8% yield) as a solid. Anal. Calcd. for C15H24N2O3 m/z 280.3. found: 281.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CO.[Pd]>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([OH:1])=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=[N:5]1
Reactant: CCOC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccccc2N)c1O
Yield: 69.2 %

Procedure:
126.3 g of 5-hydroxy-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester is dissolved in 1.6 liter methanol and 1.2 g Pd/C (10%) are added and hydrogenation is performed until H2 -uptake is finished (12 hours). After filtration the solvent is distilled off and the crystalline residue is recrystallized from dimethylformamide/ethanol to yield 78 g of 1-(2-aminophenyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid, ethyl ester as white powder having a melting point of 151°-154° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=O)=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.B#B>O1CCCC1>[CH3:18][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:21])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: O=C(O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: B#B
Solvent: C1CCOC1
Product: Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reaction time: 8 h

Procedure:
A solution of 0.01 mole of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in tetrahydrofuran is added dropwise to a chilled (0° C.) solution of 0.02 mole of diborane in tetrahydrofuran. After standing overnight the mixture is poured onto ice and the product extracted into dichloromethane. The dichloromethane layer is washed with water, dried (MgSO4) and the solvent removed to give the product of the example.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1C(OCC)=O.[Cl-].[Na+].O>CS(C)=O>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CC(C(=O)OCC)(C(=O)OCC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
The procedure in Sanchez et al., Synth. Comm., 1985, 15, 141 was followed. A mixture of triethyl 4-oxocyclohexane-1,1,3-tricarboxylate, Intermediate 1, (135.2 g, 400 mmol), sodium chloride (70.1 g, 1200 mmol), and H2O (17.30 mL, 960 mmol) in DMSO (530 mL) was stirred at 160° C. (oil bath) under N2 for 3.5 h. The cooled mixture was poured into ice-water (3 L) and extracted with EtOAc (400 mL×3). The combined extracts were washed with brine, dried (Na2SO4) then concentrated to provide the title compound (103.4 g, 397 mmol, 99% yield) as an amber oil. HPLC: 2.04 min (AP 45% at 220 nm). LCMS: m/z 243 (M+H). 1H NMR (500 MHz, CDCl3) δ ppm 1.27 (6H, t, J=7.0 Hz, 9,12-CH3), 2.37 (4H, t, J=6.9 Hz, 3,5-CH2), 2.43 (4H, t, J=6.7 Hz, 2,6-CH2), 4.23 (4H, q, J=7.2 Hz, 8,11-OCH2). 13C NMR (126 MHz, CDCl3) δ ppm 14.1 (9,12-CH3), 31.0 (3,5-CH2), 37.8 (2,6-CH2), 53.6 (4-C), 61.9 (8,11-OCH2), 170.7 (7,10-OC═O), 209.4 (1-C═O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Product: COc1ccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)cc1

Procedure:
7-Bromo-5-(4-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 106, Step 1) and p-anisoyl chloride according to the procedure of Example 106, Step 2 and purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane). MS (ESI) m/z 397/399 ([M+H]+); HRMS: calcd for C20H17BrN2O2, 396.0473; found (ESI+), 396.04740.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:23])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[ClH:11].Cl.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:13].[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)[OH:10])=[CH:4][CH:3]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccc(F)cc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 92.3 %

Procedure:
The procedure described in Example 2 was followed, using 0.8 g of 4-fluorophenyl isocyanate, 2.2 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.6 g of triethylamine and 25 ml of methylene chloride, to give 1.41 g (47% of theory) of N-(4-fluorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 250°-252° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Oc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-c2ccc(F)cc2)c(C2CC2)cc1C=O
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Manganese dioxide (16.6 g) was added to a toluene (80 mL) solution of (2-cyclopropyl-4′-fluoro-5-isopropoxybiphenyl-4-yl)methanol (5.75 g), and the mixture was stirred at 60 C for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.54 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[C:5]([F:15])=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.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(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:3]1[CH:4]=[C:5]([F:15])[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)#[N:17]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1nc(Nc2cnc3ccccc3c2)c(C#N)cc1F)C(N)=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The mixture of (R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide (120 mg, 0.46 mmol), 3-aminoquinoline (150 mg, 1.0 mmol), Pd(OAc)2 (22 mg, 0.11 mmol), racemic BINAP (68 mg, 0.11 mmol) and fine-powder cesium carbonate (0.50 g, 1.65 mmol) in 20 mL dioxane was degassed using argon stream for 3 min. It was then stirred at 100° C. in argon atmosphere for overnight. The mixture was cooled to RT, concentrated in vacuo, taken into 200 mL EtOAc and 50 mL water. The organic phase was separated and washed with brine. It was dried, concentrated and purified using silica flash column (35% EtOAc in DCM) to give (R)-2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)butanamide. It was dissolved in 4 mL DMSO. To it were added 2 mL 50% H2O2 and then powder potassium carbonate (91 mg, 0.66 mmol). The mixture was stirred at RT for 30 min. It was diluted with 4 mL 1N HCl. The mixture was subjected to reverse prep HPLC to isolate the title compound as HCl salt (102 mg).