Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[OH:20])[CH2:15][CH2:14]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:46].[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N+:13]3([O-:46])[CH2:14][CH2:15][CH:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][CH:22]=4)([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=4)[OH:20])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][N+]1(Cc2ccc(OCC3CC3)cc2)CCC(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A stirred solution of 10.0 grams (0.018 mole) of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine in methylene chloride was cooled to 0° C., and 3.1 grams (0.01 2 mole) of 50% 3-chloroperoxybenzoic acid was added in two portions. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time, the reaction mixture was poured into aqueous 5% sodium hydroxide solution. The organic layer was separated and washed with aqueous 5% sodium hydroxide solution. The organic layer was then filtered through phase separated silicone treated paper. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxy-methyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([CH2:16]O)[NH:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O.ClCCl>[Cl:3][CH2:16][C:14]1[NH:13][N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:15]=1
Reactant: OCc1cc(-c2ccccc2)n[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cc(-c2ccccc2)n[nH]1

Procedure:
At 20° C., 6.1 ml of thionyl chloride and 10 drops of dimethylformamide are added to a solution of 7.3 g (42.0 mmol) of (3-phenyl-1H-pyrazol-5-yl)methanol in 220 ml of dichloromethane. The mixture is then boiled under reflux for 12 h. The solvent is then removed from the reaction mixture. The residue is taken up in 100 ml of dichloromethane, and a saturated sodium bicarbonate solution is added to the mixture until a pH of from 6 to 7 is established. The mixture is then freed from the solvent under reduced pressure and dried. This gives 5.65 g of the desired product which is reacted further without further purification; log P(HCOOH): 2.05 with MS (ESI): 193.1/195.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH2:19][CH3:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)O)=[CH:4][CH:3]=1.[CH3:21][CH:22](C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH2:19][CH3:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:23][CH:22]=[CH2:21])=[CH:4][CH:3]=1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Reactant: CCCC(c1ccc(Br)cc1)C(O)c1ccc(Cl)cc1
Product: C=CCC(c1ccc(Cl)cc1)C(CCC)c1ccc(Br)cc1

Procedure:
The title compound was prepared from the intermediate from Step D using the conditions described in INTERMEDIATE 1, Step D. The title compound is obtained as a 2.1:1 mixture of diastereomers. 1H NMR for major diastereomer (500 MHz, CDCl3): δ 7.44 (d, J=8.5 Hz, 2H); 7.28 (d, J=8.3 Hz, 2H); 7.05 (d, J=8.2 Hz, 2H); 7.02 (d, J=8.4 Hz, 2H); 5.46-5.35 (m, 1H); 4.82-4.71 (m, 2H); 2.77-2.62 (m, 2H); 2.14-2.02 (m, 2H); 1.35-1.25 (m, 2H); 1.05-0.89 (m, 2H); 0.67 (t, J=7.3 Hz, 3H). LC1 4.66 min. Not ionized
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[C@@H:4]12[N:11](C)[C@@H:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][C:5]2=O.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C>[CH3:3][N:2]1[CH:4]2[CH2:10][CH2:9][CH:1]1[CH:7]([C:8]#[N:11])[CH2:6][CH2:5]2
Reactant: CN1[C@@H]2CCC(=O)[C@H]1CC2
Reactant: [C-]#[N+]C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: CN1C2CCC(C#N)C1CC2
Temperature: 0 °C

Procedure:
Methyl isocyanide (5.04 g., 0.026 mol) was added to (±)-tropan-2-one (2 g., 0.0143 mol) in dimethoxyethane (80 ml) and the solution cooled to 0° C. Ethanol (2 ml) was added followed by addition of potassium tert-butoxide (5.64 g, 6.05 mol). The mixture was then heated at 50° C. for three hours, cooled and poured into a saturated potassium carbonate solution (300 ml). This was extracted with ethyl acetate (3×100 ml) and the combined extracts dried (K2CO3), filtered and evaporated to give a crude oil which was abosorbed on alumina (40 g, grade 1 neutralised by addition of 10% water) from ethereal solution. The solution was eluted with a progressively graded mixture of ether, ethyl acetate and methanol to give 8-methyl-8-azabicyclo[3.2.1]octane-2nitrile (1.1 g--46%) as an oil.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.CN(C)C(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:43]1[S:44][C:45]2[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=2[N:47]=1>C(OCC)(=O)C>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:43]4[S:44][C:45]5[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=5[N:47]=4)[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 25-mL round-bottom flask equipped with a stir bar was added sequentially 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1H) (0.525 g, 1.29 mmol), 3.6 mL of N,N-dimethylacetamide, cesium carbonate (1.08 g, 3.31 mmol), and methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (1.12 g, 3.87 mmoles). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60° C. and stirred for 1 h. The reaction slurry was allowed to cool to RT, and was diluted with 200 mL of ethyl acetate and washed with water (3×30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gel chromatography (40 g silica column) with a 15 min gradient of 10% to 60% ethyl acetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give the desired product as a white crystalline solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1.[Cu]I.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>[C:16]([O:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 70 %

Procedure:
A solution (0.1 M) of ethyl 5-bromo-4-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate in THF was treated with trimethylsilylacetylene (1.3 eq.), Et3N (1.5 eq.), CuI (0.04 eq.) and PdCl2(PPh3)2 (0.01 eq.). The solution was heated at 50° C. for 3 h. After cooling down, it was filtered through a pad of celite and washed with AcOEt. The organic layer was washed with brine and dried then concentrated and the residue was purified by flash chromatography on silica gel (1:19 AcOEt/petroleum ether) to afford the title compound (70%) as a solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH:33][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1cnn(CCN2CCCC2)c1
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: FC(F)(F)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
[1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.100 g, 0.33 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.078 g, 0.43 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (78 mg, 52%). MP=205-207° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.35 (s, 1H), 8.76 (d, J=6.44 Hz, 1H), 8.38 (d, J=8.00 Hz, 2H), 7.08-7.93 (m, 3H), 7.84 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=7.08 Hz, 1H), 4.17 (t, J=6.37 Hz, 2H), 2.80 (t, J=6.24 Hz, 2H), 2.45 (s, 4H), 1.64 (s, 4H). MS=442 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[S:10].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:41][CH3:42])=[C:16]([CH:40]=1)[C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([O:38][CH3:39])=[C:26]([S:30]([NH:33]C(NC)=O)(=[O:32])=[O:31])[CH:27]=2)[O:22][CH2:21]1)=[O:18].C>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:41][CH3:42])=[C:16]([CH:40]=1)[C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([O:38][CH3:39])=[C:26]([S:30]([NH:33][C:9]([NH:8][CH3:7])=[S:10])(=[O:32])=[O:31])[CH:27]=2)[O:22][CH2:21]1)=[O:18]
Reactant: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
1.65 g (12 mmol) of powdered potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate were added to 1.64 g (4 mmol) of 3-(5-fluoro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman (Example 9) in 10 ml of dry DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice-water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. The product had a melting point of 221°-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[CH3:30][N:31]1[C:35]([CH:36]=O)=[CH:34][N:33]=[CH:32]1.ClCCCl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:36][C:35]4[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=4)[CH2:26][CH2:27]3)=[O:21])=[N:18][N:19]=2)(=[O:11])=[O:12])=[C:5]([CH3:29])[CH:4]=1
Reactant: Cn1cncc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4cncn4C)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (42 mg, 0.10 mmol), 1-methyl-1H-imidazole-5-carbaldehyde (13 mg, 0.12 mmol), STAB (42 mg, 0.2 mmol) DCE (0.8 mL) and a few 4 Å molecular sieves. The crude product was purified using prep method D.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12](O)[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]([CH:9]=1)[O:5][CH2:4][C@H:2]1[CH2:3][O:1]1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Reactant: OC[C@H]1CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(OC[C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a mixture of (2S)-oxiran-2-ylmethanol (296.3 mg, 4.0 mmol), 5-methoxy-2-nitrophenol (676.6 mg, 4.0 mmol) and triphenyl phosphine (1.05 g, 4.0 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD, 704.6 mg, 4.0 mmol) in THF (5 mL) dropwise at room temperature. After addition was completed the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum spirit) to give the subtitled compound (650 mg).
Reaction SMILES: [F:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:26]=[N:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[F:1][C:2]1[C:12]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:26]=[N:27][CH:28]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cn1c(=O)oc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CCS(=O)(=O)Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1cncc(-c2cc3c(cc2F)oc(=O)n3C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A flask was charged with 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (220 mg, 0.751 mmol), N-(5-bromopyridin-3-yl)ethanesulfonamide (133 mg, 0.5 mmol), K3PO4 (212 mg, 1.0 mmol) and Pd(PPh3)4 (28.9 mg, 0.025 mmol). The flask was flushed with N2 and DMF (5 mL) was added. The mixture was stirred under N2 at 100° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and filtered through a pad of celite. The celite pad was washed with EtOAc (100 mL) and the combined organic phase was washed with water (50 mL*2) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0 to 80% EtOAc-heptane gradient to give N-(5-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) d ppm 1.23 (t, J=7.33 Hz, 3H) 3.21 (q, J=7.33 Hz, 2H) 3.38 (s, 3H) 7.53 (d, J=6.57 Hz, 1H) 7.58 (d, J=10.11 Hz, 1H) 7.79 (q, J=1.85 Hz, 1H) 8.47 (d, J=2.27 Hz, 1H) 8.49 (t, J=1.52 Hz, 1H) 10.20 (s, 1H). HRMS: (ESI) m/z 352.0769 [(M+H)+Calcd for C15H15FN3O4S 352.07618].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[N:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:27][CH3:28])[CH2:12][CH2:13][CH3:14]>CC(O)C>[CH2:11]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:27][CH3:28])[CH2:12][CH2:13][CH3:14]
Reactant: Clc1ccc2c(c1)NCC2
Reactant: CCCCOc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: CCCCOc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1OC
Yield: 43 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 43% yield from 6-chloro-indoline (1.1 eq.) and 7-butoxy-4-chloro-6-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 126°-132° C.; GC-MS: 383 (M+); anal. RP18-HPLC RT: 6.22 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CNC1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[F:14][CH:2]([F:1])[C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccnc(C(F)F)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccnc(C(F)F)c1F
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(difluoromethyl)-3-fluoroisonicotinate (0.44 g, 2.1 mmol, from Step 4) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.45 g, 11 mmol) in water (10 mL). The reaction was stirred for 2 hours. The reaction mixture was acidified by the addition of a solution of citric acid. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated to afford product, which was used without further purification in Step 6. H NMR (300 MHz, CD3OD): δ 8.57 (d, 1H), 7.99 (dd, 1H), 6.96 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].C(O)C.[BH4-].[Na+]>O>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[CH:4]([C:3]1[CH:15]=[C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:17]=[CH:18][C:2]=1[CH3:1])[OH:5]
Reactant: Cc1cc(C)c(C(=O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Temperature: 50 °C
Reaction time: 10 h
Yield: 78.9 %

Procedure:
To a suspension of 7.3 g of 2-methyl-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone is 50 ml of ethanol is added a solution of 1 g of sodium borohydride in 10 ml of water. After the mixture is stirred at 50° C. for 10 hours, the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 5.8 g of α-(2,4,6-trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 190°-191° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[C:5]2[CH2:11][N:10]([C:12]3[N:16]([CH2:17][CH3:18])[N:15]=[C:14]([CH:19]4[CH2:21][CH2:20]4)[CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:48])[C:37]=2B2OC(C)(C)C(C)(C)O2)[N:32]([S:49]([C:52]2[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=2)(=[O:51])=[O:50])[N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH:19]1([C:14]2[CH:13]=[C:12]([N:10]3[CH2:9][CH2:8][C:6]4[N:7]=[C:2]([C:37]5[C:36]([CH3:48])=[CH:35][CH:34]=[C:33]6[C:38]=5[C:30]([CH3:29])=[N:31][N:32]6[S:49]([C:52]5[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=5)(=[O:50])=[O:51])[N:3]=[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][C@H:23]5[CH3:28])[C:5]=4[CH2:11]3)[N:16]([CH2:17][CH3:18])[N:15]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3c(B4OC(C)(C)C(C)(C)O4)c(C)ccc32)cc1
Reactant: CCn1nc(C2CC2)cc1N1CCc2nc(Cl)nc(N3CCOC[C@H]3C)c2C1
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
Product: CCn1nc(C2CC2)cc1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc(N3CCOC[C@H]3C)c2C1
Temperature: 130 °C

Procedure:
To a solution of (R)-4-(2-chloro-6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.116 g, 0.288 mmol) in DME (1.4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole (0.129 g, 0.302 mmol), Pd(Ph3P)4 (0.033 g, 0.029 mmol) and aqueous Na2CO3 (0.43 mL, 2 M). The mixture was sparged with argon and heated in a microwave reactor at 130° C. for 1 h 20 min. The mixture was filtered and concentrated under reduced pressure. Purification by FCC (40-100% EtOAc/heptane) provided the title compound (R)-4-(6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine. MS (ESI+) m/z 667.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[CH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:23](#[N:28])/[CH:24]=[CH:25]/[C:26]#[N:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]3)=[C:25]([C:26]#[N:27])[C:24]=2[C:23]#[N:28])=[CH:4][CH:3]=1
Reactant: N#C/C=C/C#N
Reactant: CCCCC[C@H]1CC[C@H](C=CC=Cc2ccc(F)cc2)CC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(F)cc3)c(C#N)c2C#N)CC1

Procedure:
Using 1-(p-fluorophenyl)-4-(trans-4'-n-pentylcyclohexyl)-1,3-butadiene and fumaronitrile, 3-(p-fluorophenyl)-6-(trans-4'-n-pentylcyclohexyl)phthalonitrile was obtained by the same method as in Example 1. m.p. was 102.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].O1CCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]([C:22](=[O:23])[CH2:21][Cl:20])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1ccc(N(C(=O)CCl)c2c(F)c(F)cc(F)c2F)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylanilin (2.05 g) and chloro acetylchloride (1.99 g) is mixed without solvent and heated with stirring to 90° C. under nitrogen for 20 h. Tetrahydrofurane (10 ml) and aqueous sodium bicarbonate are added after cooling and stirring is continued for about 1 hour. The organic phase is diluted with toluene and washed with water three times and dried over magnesium sulfate. Evaporation and chromatography of the residue (silica, toluene) gave N-(2′,3′,5′,6′-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline (1.84 g) as a solid which is recrystallised from heptane, mp.: 72° C.