Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccc(C#N)cn1
Yield: 52.3 %

Procedure:
The title compound (1.54 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g) and 2-chloro-5-cyanopyridine (1.29 g) in the presence of diisopropylethylamine (1.21 g) according to the method of D28.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1>>[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][N:19]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Product: CC(C)(C)C(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 42 %

Procedure:
The title compound was prepared from 2,2-Dimethyl-propionyl chloride and the amine of example 12, in 42% yield, using the procedure described in example 3.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.C1([Li])C(C)=C(C)C=C(C)C=1C>C1COCC1.CCOCC>[C:2]1([B:17]([OH:20])[OH:18])[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11]
Reactant: COB(OC)OC
Reactant: Cc1cc(C)c(C)c(Br)c1C
Agent: [Li]CCCC
Agent: [Li]c1c(C)c(C)cc(C)c1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C)c(B(O)O)c1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.2 mol of 3-bromodurene is reacted in 800 ml of absolute THF by means of 0.25 mol of butyllithium under inert conditions at −78° C. On completion of the BuLi addition, the reaction mixture is stirred at −78° C. for another 1 h and then allowed to thaw. A 2 l flask is then initially charged with 500 ml of absolute ether and 0.3 mol of trimethyl borate at −78° C. and the duryllithium prepared beforehand is added dropwise within a period of 30 min. The mixture is then allowed to thaw and the reaction mixture is stirred for another 12 h. Finally, the reaction mixture is poured onto 2 N HCl-ice mixture and hydrolyzed for 12 h, the organic phase is extracted and concentrated, and the residue is admixed with pentane to precipitate out the product. The product is filtered off with suction and dried under reduced pressure mp: 101-3° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(Cl)c1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[(3-chloro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 4) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 484.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:17]([CH3:20])[CH2:18][OH:19].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:52]([O:54][C:55](=[O:67])[CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][C:63](O)=[CH:62][C:59]=2[S:60][CH:61]=1)[CH3:53]>C1(C)C=CC=CC=1>[CH2:52]([O:54][C:55](=[O:67])[CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][C:63]([O:19][CH2:18][CH:17]([C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=4)[S:6][C:2]=3[CH3:1])[CH3:20])=[CH:62][C:59]=2[S:60][CH:61]=1)[CH3:53]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)CO
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1csc2cc(OCC(C)c3nc(-c4ccc(C(F)(F)F)cc4)sc3C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution of 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (226 mg, 0.75 mmol) in toluene (4.0 mL) is degassed and filled with nitrogen for 3 times. O this solution is added 1,1′-(azodicarbonyl)-dipiperidine (190 mg, 0.75 and mmol) and tributylphosphine (0.186 mL, 0.75 mmol) under nitrogen at 0° C., followed by addition of (6-hydroxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (120 mg, 0.5 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded on silica gel column. Chromatography yields the title compound (250 mg).
Reaction SMILES: [Cl-:1].[K+].[Cl:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[CH:7]=[O:8].ClCl>ClC1C=CC=CC=1C(F)(F)F>[Cl:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:7]([Cl:1])=[O:8]
Reactant: O=Cc1cc(F)c(F)c(Cl)c1F
Reactant: [Cl-]
Agent: ClCl
Agent: FC(F)(F)c1ccccc1Cl
Agent: [K+]
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Yield: 376.2 %

Procedure:
100 ml of 2-chlorobenzotrifluoride and 4.5 g of potassium chloride were placed at 110° C. in a chlorination apparatus with UV irradiation and 50 g of 3-chloro-2,4,5-trifluorobenzaldehyde in 50 ml of 2-chlorobenzotrifluoride were subsequently added dropwise with exclusion of air. After addition of 10 ml of the solution, chlorine was added at the rate at which it was absorbed. The metered addition was continued until the entire amount of the aldehyde used had reacted (gas chromatographic monitoring). Distillation of the reaction mixture gave 52 g of 3-chloro-2,4,5-trifluorobenzoyl chloride having a boiling point of 92° C./20 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:29][C:11]3[C:12](=[O:28])[N:13]([C:16]4[CH:17]=[N:18][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]5)=[CH:20][CH:21]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:29][C:11]3[C:12](=[O:28])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([O:27][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23]5)=[N:18][CH:17]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)cc2CCN1c1ccc(N2CC[C@H](O)C2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-[6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (1.246 g, 2.93 mmol) in CH2Cl2 (25 mL). Cool to 0° C. and treat with Et3N (0.61 mL, 4.39 mmol), followed by MsCl (0.25 mL, 3.22 mmol). Stir at 0° C. for 15 min and at RT for 2 h. Dilute the mixture with CH2Cl2 (50 mL). Wash with H2O (2×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% CH3OH/CH2Cl2 to give 1.21 g (82%) of the title compound. MS/ES m/z (35Cl) 504.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1nccc2ccccc12
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1nccc2ccccc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 1-bromoisoquinoline (2.06 g, 10 mmol), prepared as described in European Journal of Organic Chemistry 2002, 4181-4184, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=O)[CH2:28][O:29][C:25]=2[CH:24]=1>>[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[CH:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]4([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]4)[CH:7]=3)[CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C1COc2cc(Cl)ccc21
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC3COc4cc(Cl)ccc43)ccc2F)C1(F)F
Yield: 50.7 %

Procedure:
Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (96 mg, 302 μmol) and commercially available 6-chlorobenzofuran-3(2H)-one [CAS no 3260-78-4] (61.0 mg, 362 μmol) The (5R)-5-(5-(6-chloro-2,3-dihydrobenzofuran-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (72 mg, 153 μmol, 50.7% yield) was obtained as a light yellow foam. MS (ISN): m/z=469.1 [(M−H)−] and 471.2 [(M+2-H)−].
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH2:7]1)[CH2:4][OH:5].CO[C:27](OC)([CH3:29])[CH3:28].B(F)(F)F.CCOCC.C(Cl)Cl.CO>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:3]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:4][O:5][C:27]([CH3:29])([CH3:28])[O:1][CH2:2]1)[CH2:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)C1CCc2cc(O)ccc2C1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C2CCc3cc(O)ccc3C2)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.7 %

Procedure:
tert-Butyl 1,3-dihydroxy-2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-ylcarbamate (0.400 g, 0.00118 mol) was treated with 2,2-dimethoxypropane (20.0 mL, 0.163 mol) and p-toluenesulfonic acid monohydrate (0.0226 g, 0.000118 mol) in ethyl acetate (20.0 mL, 0.205 molat r.t. for 24 hours. The solvent was removed. 2,2-dimethoxypropane (20.0 mL, 0.163 mol) was added, followed by boron trifluoride etherate (0.150 mL, 0.00118 mol). The mixture was stirred at r.t. overnight. The mixture was quenched with saturated NaHCO3 aqueous solution, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude. Chromatograph with DCM:MeOH (100:0 to 93:7) gave a solid product (560 mg, 100%). 1H NMR (CHLOROFORM-d) δ: 6.89-6.99 (m, 1H), 6.49-6.65 (m, 2H), 6.46-6.47 (s, br, 1H), 3.99 (m, 4H), 3.13-3.30 (m, 4H), 2.69-2.85 (m, 2H), 2.10-2.39 (m, 1H), 1.56 (s, 6H), 1.37-1.50 (s, br, 9H). MS (M+Na+): 400.0.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]2[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([CH2:29][OH:30])=[CH:27][N:26]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]2[C:19]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(COc3nn(-c4ccccc4)cc3CO)oc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(COc3nn(-c4ccccc4)cc3C=O)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of [3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazol-4-yl]methanol (0.22 g), activated manganese dioxide (0.75 g) and tetrahydrofuran (10 mL) was stirred at room temperature for 3 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.19 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 176-177° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[K+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 83.7 %

Procedure:
To a solution of 1a (4 gm, 7.54 mmol) in ethanol (40 mL), 20% KOH solution (10 mL) was added. The reaction mixture was refluxed for 2 h. Ethanol was evaporated under a vacuo, and was neutralized by 6 N HCL. The combined mixture was extracted in EtOAc (3×20 mL), washed with brine solution (20 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to obtain pure compound 3,4,5-tris(benzyloxy)benzoic acid (1b) as white solid (2.78 g, 84%). Rf=0.515 (50% ethyl acetate in hexane)
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:5]([C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)=[O:6].[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23].C(N(CC)CC)C.O>ClCCl>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([C:5](=[O:6])[CH:4]([NH:3][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NC(C(=O)c1ccc2c(c1)OCO2)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(C(=O)NC(C(=O)c2ccc3c(c2)OCO3)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
2-Amino-1-benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethanone dihydrochloride (1 g, 3 mmol) was added to a stirring solution of 4-cyano-benzoyl chloride (0.459 g, 3 mmol) in dichloromethane (10 ml). Triethylamine (2 ml, 14 mmol) was added dropwise and the reaction was stirred at ambient temperature for 18 hours. Water was (50 ml) added the organics were extracted into dichloromethane. Chromatographic purification using a dichloromethane solution of ammonia in methanol (0.5% c. ammonia: 4.5% methanol: 95% dichloromethane) yielded the title compound as a pale yellow oil (0.9 g, 76%); m/z (API) 386 (M+H+, 100%).
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]2[CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:16]=2[Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 4 of Example 83 and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:28]=[CH:29][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:40])([F:41])[F:39])=[CH:31][N:32]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 32.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (262 mg, 0.73 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (102 mg, 0.36 mmol, Example X, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (355 mg, 1.1 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (2 mL), and water (0.2 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (56 mg) as a tan solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[S:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH:22]=[O:23])[CH2:17]1.Cl>CCCCCC.O1CCCC1>[OH:23][CH:22]([CH:18]1[CH2:19][CH2:20][CH2:21][S:16][CH2:17]1)[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: O=CC1CCCSC1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)C1CCCSC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
6.6 g of sodium hydride (80%) is added to 400 ml of tetrahydrofuran and the mixture is cooled to 0° C. At this temperature, 24.4 g of methyl acetoacetate is dripped in, the resulting mixture is stirred for 15 minutes, then 137.5 ml of a 1.6 molar butyllithium solution in hexane is dripped in and the mixture stirred for 30 minutes. At from 0° to 3° C., 26 g of tetrahydrothiopyran-3-carboaldehyde is dripped in and the mixture stirred for a further 30 minutes to complete the reaction. To this end, 45 ml of concentrated hydrochloric acid is carefully dripped in. The cold reaction mixture is poured into 250 ml of ice water and the organic phase is separated. The aqueous phase is extracted twice, each time with 250 ml of methyl tert-butyl ether. The combined organic extracts are washed once with 300 ml of saturated sodium chloride solution, dried with sodium sulfate and concentrated in a rotary evaporator. There is obtained 48.1 g of an oil which is used immediately for further reaction.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: Cn1ccnc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1ccnc1C(=NO)c1ccccc1
Yield: 82.1 %

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)(phenyl)methanone (20.8 g, 112 mmol) and hydroxylamine hydrochloride (19.4 g, 279 mmol) in pyridine (120 mL) was stirred 8 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (500 mL) induced precipitation of a white solid that was filtered off, washed with water (2×50 mL) and dried. A second filtration of the liquor yielded a second crop of solid. The combined crops afforded N-hydroxy-1-(1-methyl-1H-imidazol-2-yl)-1-phenylmethanimine [18.5 g, yield 80%; HPLC/MS: m/z=202 (M+H); log P(HCOOH)=0.24].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([S:27][CH3:28])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:29].[OH:30]OS([O-])=O.[K+]>C1COCC1.O.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([S:27]([CH3:28])=[O:30])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:29]
Reactant: O=S([O-])OO
Reactant: CSc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reaction time: 2 h

Procedure:
The product of example 2 (204 mg, 0.49 mmol) in THF was treated dropwise with oxone® (0.307 g, 0.5 mmol) in H2O (10 mL). The mixture was stirred at 23° for 2 h, diluted with EtOAc (100 mL) and washed with H2O (2×25 mL) and satd aq NaCl (25 mL), dried (Na2SO4), and concentrated. The residue was purified by prep hplc to afford the sulfoxide as a white powder. LC MS m/z=433 (MH+), Rt=1.70 min
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O-])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][N:10]3[CH2:11][C:12]4=[N:13][NH:14][C:15]5[C:20]4=[C:19]([CH:18]=[CH:17][CH:16]=5)[C:21]3=[O:22])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: O=C([O-])c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cccc3[nH]nc(c23)CN1CC12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.1 %

Procedure:
Lithium 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate (3.9 g, 12.1 mmol) from Step B above in THF (20 mL) was cooled in an ice bath while N,N-diisopropylethylamine (9.4 g, 72.8 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (23.0 g, 72.8 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 60:36:4 dichloromethane/methanol/concentrated ammonium hydroxide) to give 4-(quinuclidin-4-ylmethyl)-3,4-dihydropyrazolo[3,4,5-de]isoquinolin-5(1H)-one as a yellow oil (468 mg, 13%): 1H NMR (500 MHz, CD3OD) δ 7.62-7.60 (m, 1H), 7.54-7.53 (m, 2H), 5.15 (s, 2H), 3.53 (s, 2H), 2.93 (t, J=8.0 Hz, 6H), 1.67 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 297 (M+H).