Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OCCCO2)=[C:16]([F:26])[C:15]=1[O:27][CH3:28].[F-].[K+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:27][CH3:28])[C:16]=2[F:26])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: N#Cc1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C#N)c(Cl)c(N)c2F)c1F
Temperature: 75 °C
Yield: 57.2 %

Procedure:
A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549 g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile (6.75 mL) and water (2.25 mL). The mixture was stirred and sparged with a nitrogen atmosphere. Pd(PPh3)2Cl2 (63mg, 0.1 mmol) was added, and the mixture was again sparged with nitrogen. The solution was then heated to 75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formed and was collected by filtration, washed with water and dried under vacuum to give the product (0.34 g) as an off-white solid. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried, and concentrated. Purification by silica gel chromatography gave additional product (0.12 g) as a white solid. Total yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz), 143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz), 133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m), 122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F), −133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2](=[O:27])[C@@H:3]([NH:19]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:19][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[C:2]([NH2:1])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(C[C@H](N)C(N)=O)cc2)cc1

Procedure:
(S)-tert-Butyl 1-amino-3-(4′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamate (Example 3, step (ii), 3.13 g) was dissolved in dichloromethane (30 mL) and TFA (1.32 mL) was added. The dichloromethane was distilled off on a rotary evaporator at atmospheric pressure to leave ˜5 mL of solvent. The reaction was monitored by HPLC/MS and when complete was partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaporated. The resulting solid was purified by chromatography on silica eluting with ethyl acetate then ethyl acetate containing 10% methanol to afford the sub-titled compound (1.95 g).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:27][CH2:26][CH:25]([NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])[CH3:35]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30 mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16 h). The mixture was basified to pH=10 with saturated aqueous Na2CO3 and extracted with EA (2×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)-N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 98%) as a light yellow oil. Mass calculated for C25H40N2O=384.6; found: [M+H]+=385.2.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[C:15]([CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22])#[N:16].[H-].[Na+]>CN(C=O)C>[C:15]([CH:17]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1)[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22])#[N:16]
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: COc1nc(Cl)c([N+](=O)[O-])c(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c([N+](=O)[O-])c(C(C#N)c2cc(C)cc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloro-2,6-dimethoxy-5-nitro-pyrimidine (0.45 g, 2.05 mmol, 1.05 eq., prepared according to Cushman et al. J. Org. Chem. 2004, 69, 601-612) and 3-cyanomethyl-5-methyl-benzonitrile (0.305 g, 1.95 mmol, 1.0 eq.) was dissolved in DMF (3.36 mL) and cooled to 0° C. 60% Sodium hydride (0.157 g, 3.92 mmol, 2.0 eq.) was added portionwise and the reaction was stirred at 0° C. for 1 h, then rt for 1 h. The reaction was cooled to 0° C. and quenched with saturated ammonium chloride solution. The pH was adjusted to ˜6.0 with 1N HCl and mixture was extracted with ethyl ether. The organic layer was washed with water (2×), dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 20 to 50% ethyl acetate/hexane) to give a yellow foam (0.6514 g, 98%). 1H NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 5.64 (s, 1H), 4.05 (s, 6H), 2.34 (s, 3H). Mass spectrum: 338.0 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#N)=[C:4]([O:11][CH3:12])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:23]1CCCC1>>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:23])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C#N
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc(Br)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-bromo-2-methoxy-6-methyl-benzonitrile (2.8 g, 12.38 mmol) in tetrahydrofuran (24.8 ml) is added diisobutylaluminium hydride (1.2 M in toluene) (24.8 ml, 29.7 mmol) at −78° C. The reaction mixture is slowly warmed to RT and stirred at RT for 18 h. The reaction is quenched with 1 M hydrochloric acid at 0° C. The resulting mixture is stirred at RT for 1 h and extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (40 ml), dried over sodium sulfate and evaporated. The crude product is purified by column chromatography (silica gel, 1.5% ethyl acetate/hexane) yielding 4-bromo-2-methoxy-6-methyl-benzaldehyde (1.25 g, 5.45 mmol, 44%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([O:17][CH2:18][C:19]([O:21]CC)=O)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH:26]([OH:38])[CH2:27][N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>CCO>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][CH2:37][N:28]1[CH2:27][CH:26]([OH:38])[CH2:25][NH:24][C:19](=[O:21])[CH2:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)COc1cccc2ccc(N3CCOCC3)nc12
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2ccc(N3CCOCC3)nc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred mixture of ethyl 2-((2-morpholinoquinolin-8-yl)oxy)acetate (100 mg, 0.316 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (65 mg, 0.316 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave conditions then after evaporation of solvent, the reaction mixture was purified by prep-HPLC to afford the title product (14 mg, Yield 10%). 1H NMR (400 MHz, MeOD) δ=8.04 (d, J=9.3 Hz, 1H), 7.43-7.36 (m, 1H), 7.23-7.16 (m, 3H), 7.10-7.00 (m, 3H), 6.97 (d, J=4.8 Hz, 1H), 4.77 (s, 2H), 3.96 (t, J=6.3 Hz, 1H), 3.87-3.83 (m, 4H), 3.77-3.72 (m, 4H), 3.63-3.53 (m, 2H), 3.52-3.45 (m, 1H), 3.40 (d, J=6.3 Hz, 1H), 2.83 (d, J=5.8 Hz, 2H), 2.75-2.67 (m, 2H), 2.56-2.37 (m, 2H). LCMS (m/z): 477.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].Cl[C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:21][C:20]3[CH2:22][N:23]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:24][C:19]=3[CH2:18]2)=[CH:13][CH:12]=1>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][C:19]3[CH2:24][N:23]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:36])[F:35])=[O:26])[CH2:22][C:20]=3[CH2:21]2)=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(Cl)nn1)C2
Reactant: OCc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCc3nccs3)nn1)C2
Reaction time: 0.5 h

Procedure:
Thiazol-2-ylmethanol (64 mg, 0.56 mmol) was dissolved in 2 ml of anhydrous DMF. After adding sodium hydride (42 mg, 55 percent suspension in oil), the mixture was stirred for 30 min, [5-(6-chloropyridazin-3-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl](2-trifluoromethylphenyl)methanone (100 mg, 0.25 mmol) was added, and the mixture was stirred at 150° C. for 30 h. After concentrating, water and ethyl acetate were added, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 6 mg (5%), M+H+: 474.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:4]=1[C:5]([N:7]=[C:8]=[O:9])=[O:6].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C:8]([NH:30][C:27]1[CH:28]=[N:29][C:24]([S:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:25][CH:26]=1)=[O:9])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(Sc2ccc(Cl)cc2)nc1

Procedure:
2,6-Dimethoxybenzoyl isocyanate (2.07 grams; 0.01 mole) and 6-(4-chlorophenylthio)-3-aminopyridine (2.37 grams; 0.01 mole) were mixed in 100 ml. of ethyl acetate and stirred at room temperature for 3 hours. Solvent was removed in vacuo and the product crystallized from hexanes-ethyl acetate, yield 0.6 gram, m.p. 172°-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:42])[N:34]=2)[CH:31]=1>CN(C=O)C>[CH3:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:42])[C:35]=1[C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:31][N:30]2[N:32]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: Cc1cccc(C)c1-c1nc2ccc(CCl)cn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4c(C)cccc4C)nn3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (WO05/086661) (0.2 g, 0.87 mmol) in DMF (20 mL) is added Cs2CO3 (0.84 g, 2.59 mmol) and 6-(chloromethyl)-2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.187 g, 0.69 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice cold water and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane to give the title compound as colourless liquid (0.225 g, 55%). LCMS m/z 468 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Na+].[CH3:11][S:12]([O-:14])=[O:13]>CS(C)=O>[CH3:11][S:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
4-Chlorobenzaldehyde (5.0 g, 36 mmol) and methanesulfinic acid sodium salt (4.04 g, 40 mmol) are dissolved in dry DMSO under argon. The stirred reaction mixture is heated at 100° C. for 17 hours then poured onto water (50 ml). The white precipitate is removed by filtration and dried under vacuum to afford the title compound (2.2 g).
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:12]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:28]1([CH3:31])[CH:27]=[CH:26][C:25]([S:22]([N:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[C:11]([CH:9]3[CH2:10][CH:8]3[CH:6]=[CH2:1])=[CH:12]2)(=[O:23])=[O:24])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C3CC3C=O)c3cc(C#N)ccc32)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CC1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Butyl lithium (1.4 ml of 2.4M in hexane, 3.36 mmol) was added drop wise over a five min period under a nitrogen atmosphere to a stirred solution of methyltriphenylphosphonium bromide (1.186 g, 3.32 mmol) in dry THF (25 ml). The solution was stirred for 30 min at ambient temperature and then added dropwise to a solution of 3-(2-formyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (1.10 g, 3.018 mmol) in 25 ml THF. The mixture was stirred for 24 hr, and then quenched with saturated aqueous ammonium acetate (2 ml). The mixture was concentrated in vacuo and then extracted with ethyl acetate (20 ml). The ethyl acetate extract was washed with water (10 ml), then washed with brine (10 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel using methylene chloride as the eluent to give 1-(toluene-4-sulfonyl)-3-(2-vinyl-cyclopropyl)-1H-indole-5-carbonitrile (755 mg, 71%). 1H NMR (300 MHz, CDCl3): δ8.04 (d, 1H), 7.91 (s, 1H), 7.74 (d, 2H), 7.56 (d, 1H), 7.54 (s, 1H), 7.25 (m, 2H), 5.57 (m, 1H), 5.19 (d, 1H), 5.01 (d, 1H), 2.36 (s, 3H), 1.86 (m, 1H), 1.63 (m, 1H), 1.16(m, 2H). MS m/e 363.16 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH3:16])[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[N:20][CH:21]=1)[CH3:27]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)nc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 300 mg (1.316 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-chroman (compound 4s) and 245.6 mg (1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml of triethylamine was placed in a pressure tube and a stream of nitrogen was bubbled through the solution for 15 min. The tube was then flushed with argon and a finely ground mixture of 100 mg (0.1425 mmol) of bis (triphenylphosphine) palladium (II) chloride and 50 mg (0.2625 mmol) of cuprous iodide was added to the solution. The pressure tube was then sealed and the reaction mixture heated at 60 degrees C. for 72 h. The mixture was cooled to room temperature and the triethylamine removed under vacuum. The residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): & 1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J~7.2 Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J~7.2 Hz), 6.70 (1H, s), 7.55-7.61 (2H, m), 8.28 (1H, dd, J~8.2 Hz, 2.1 Hz), 9.22 (1H, d, J~2 1 Hz). MS exact mass, m/e 377.1982 (calcd. for C24H27O3N, 377.1991).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C([Li])CCC.[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:36])([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: COCn1ccnc1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 14 h

Procedure:
To a solution of 55 mg (0.49 mmol) of 1-methoxymethyl-1H-imidazole in 5 ml of THF at −78° C. was added 0.20 ml (0.50 mmol) of a 2.5 M solution of n-butyllithium in hexanes and the resultant mixture was stirred at −78° C. for 30 mins. After this time, a solution of 160 mg (0.47 mmol) of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) in 2 ml of THF was added and the resultant mixture stirred at −78° C. for a further 2 h, and then at room temperature for 14 h. After this time the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 3.09 (s, 3H), 3.19 (s, 3H), 4.90 (s, 2H), 5.16 (brs, 1H), 7.07–7.16 (m, 4H), 7.42–7.62 (m, 7H). Mass Spectrum (CI+) m/e=456.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=[CH:7]2.[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2
Reactant: CCOC(=O)c1ccc2cccc(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965), a mixture of ethyl 8-amino-2-naphthoate (5.2 g, 0.024 mol), 1N NaOH (48 mL, 0.048 mol), and dioxane (50 mL) was stirred at room temperature for 3 hours. The dioxane was removed under reduced pressure, and the aqueous phase was diluted with H2O (100 mL) and extracted with ether. Neutralization with acetic acid produced a yellow precipitate which was collected by filtration (3.2 g, 71%), m.p. 221°-223° C.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][C:2]([F:7])([F:1])[CH2:3]2)[N:12]=[CH:11][N:10]=1
Reactant: FC1(F)CCNC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC1(F)CCN(c2cc(Cl)ncn2)C1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A solution of 3,3-difluoropyrrolidine (215 mg, 1.5 mmol), 4,6-dichloro-pyrimidine (223 mg, 1.5 mmol) and DIPEA (194 mg, 1.5 mmol) in 1,4-dioxane (3.0 mL) was heated at 100° C. for 16 hours. The reaction was cooled to room temperature and then partitioned between EtOAc and water. The organic phase was separated and washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was separated with flash chromatography (25+S Biotage, 20% EtOAc/pentane) to afford 160 mg (48.6%) of 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidine as a solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[S:34][N:33]=[CH:32][N:31]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCC[C@@H]2c2ccccc2)cc1F
Yield: 0.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (220 mg, 374 mmol) prepared in Example 6a, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (155 mg, 95%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([C:8]([CH3:10])([CH3:9])[C:6]=2[CH:7]=1)[C:13]3=4
Reactant: CC(C)(O)c1cc(Br)ccc1-n1c2ccccc2c2ccccc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-n2c3ccccc3c3cccc1c32
Temperature: 60 °C

Procedure:
16.4 g (43.6 mmol) of 2-(5-bromo-2-carbazol-9-ylphenyl)propan-2-ol are dissolved in 1200 ml of degassed toluene, a suspension of 40 g of polyphosphoric acid and 28 ml of methanesulfonic acid is added, and the mixture is heated at 60° C. for 1 h. The batch is cooled, and water is added. A solid precipitates out and is dissolved in methylene chloride/THF (1:1). The solution is carefully rendered alkaline using 20% NaOH, the phases are separated and dried over MgSO4. The solid obtained is washed by stirring with heptane. Yield: 14.8 g (40 mmol), 95% of theory, purity according to 1H-NMR about 95%.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[O:33]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]1>>[ClH:1].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH:20][C:38]([C:35]4[CH:36]=[CH:37][O:33][CH:34]=4)=[O:39])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reactant: O=C(O)c1ccoc1
Agent: Cl
Product: O=C(Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2)c1ccoc1

Procedure:
Example 63 was prepared as a yellow solid from Example 26 and 3-furoic acid as described for Example 62.