Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12]CC)=[O:11])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O>[F:16][C:2]([F:1])([F:15])[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(C(F)(F)F)nc1O
Yield: 52 %

Procedure:
A solution of ethyl 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylate (5.00 g, 19.4 mmol) and NaOH (0.93 g, 23.3 mmol) in H2O (20 mL) was stirred at 60° C. for 15 h. The reaction was acidified (conc. HCl) and concentrated until a solid began to form. The solid was filtered and dried to give 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylic acid (2.1 g, 53% yield); 1HNMR (DMSO-d6) δ 8.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: NC1CCCC(O)C1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
A suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100 mg, 0.204 mmol, obtained from Example 7, Step B), 3-aminocyclohexanol (70.5 mg, 0.612 mmol), Cu(I)I (7.77 mg, 0.0408 mmol), K2CO3 (141 mg, 1.02 mmol) and L-proline (9.39 mg, 0.082 mmol) was stirred in DMSO (5 mL) and heated to 100° C. for 12 hours. Water (5 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer washed with water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (47 mg, 48.3% yield) as a brown oil. LRMS (APCI pos) m/e 694.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>C(Cl)Cl>[Cl:11][C:4]1[N:3]=[C:2]([NH:15][CH2:12][CH:13]=[CH2:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: ClCCl
Product: C=CCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 18 h

Procedure:
2,6-Dichloro-3-nitropyridine (71-1, 10 g, 51.8 mmol, 1.0 equiv) was added to anhydrous DCM (207 mL) and cooled to −15° C. TEA (7.57 mL, 53.9 mmol, 1.04 equiv) was then added followed by allyl amine (4.05 mL, 53.9 mmol, 1.04 equiv) over 12 h via syringe pump. Following this duration, the reaction vessel was removed from the −15° C. bath and allowed to gradually warm to RT. After 18 h, the reaction was quenched with 0.2M citric acid (100 mL) and diluted with CH2Cl2 (40 mL). The layers were separated and the organics were washed an additional time with 1×100 mL 0.2M citric acid. Washed combined organics with 2×100 mL sat. NaHCO3, dried over Na2SO4, filtered and concentrated to give an orange oil. The crude material was carried onward without further purification. LRMS (M+H)+: observed=214.0, calculated=213.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: COc1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 97 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-anisaldehyde as given in Example 11. 1-Nitro-5-(p-methoxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained with a yield of 97%. M.p.: 181°-183° C.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C.O>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCC(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of thioanisole (5.0 g) and propionyl chloride (3.9 ml) at 0° C. in dichloroethane (80 ml) was added AlCl3 (6.4 g) in portions. The mixture was stirred 12 hours at ambient temperature, poured into water (200 ml) and conc. HCl (2 ml), then extracted with CH2Cl2. The extract was reduced to dryness to provide the title compound mp 60°-61° C. after purification by chromatography on silica gel.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:15][C:10]2[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1ncccc1/C=C/c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ncccc2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
In 10 ml of pyridine was dissolved 0.8 g of the (E)-3-(2-phenylethenyl)-2-aminopyridine obtained in Reference Example 1. To this solution was added 0.92 g of p-methoxyphenylsulfonyl chloride gradually under ice-cooling and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated off and the resulting residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=9/1). The crystal crop thus obtained was recrystallized from ethanol to provide 0.77 g of the desired compound (yellow plates). m.p. 152-155° C. Elemental analysis for C20H19N2O3S
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[NH2:17][S:14]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)(=[O:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(N)(=O)=O)C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3S)-pyrrolidin-3-ylcarbamate (1.3 g) in dioxane (50 ml) was added sulfamide (1.55 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 nm) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.44 g
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[S:6]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:7]1=2.ClC1C=CC=C(C(OO)=[O:40])C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:40]=[S:6]1[C:7]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])=[CH:11][C:8]=2[CH2:9][CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2=O

Procedure:
The product from Example 26 is treated with one equivalent of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.Cl[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]1([CH2:19][O:20][CH2:23][CH2:24][CH2:25][NH2:26])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: NCCCCl
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Agent: Cl
Product: NCCCOCc1scc2c1-c1ccccc1Sc1ccccc1-2

Procedure:
Starting from the alcohol 15 (0.27 mmole) and 3-chloropropylamine-hydrochloride (2.7 mmoles), an oily product was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: COCCCBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: COCCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-bromo-3-methoxypropane according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C13H14N4O, 243. Found, 243.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:4]=[CH:5][CH:6]=1)(=[O:28])=[O:27]
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1-c1cccc(COS(C)(=O)=O)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product from Step C (1 g, 4.42 mmole) in dichloromethane (10 mL) was added triethylamine (0.54 g, 5.3 mmol) followed by methanesulfonyl chloride (0.6 g, 5.3 mmol) dropwise. The mixture was stirred at room temperature for 3-4 h. It was then washed with water and brine, and dried over magnesium sulfate, and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: [Br-:1].[Br-].O1CCOCC1.[C:9]([C:12]1[CH:13]=[CH:14][C:15]([O:30][CH2:31][CH3:32])=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[C:21]([CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)(=[O:11])[CH3:10]>O1CCOCC1>[Br:1][CH2:10][C:9]([C:12]1[CH:13]=[CH:14][C:15]([O:30][CH2:31][CH3:32])=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[C:21]([CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)=[O:11]
Reactant: [Br-]
Reactant: CCOc1ccc(C(C)=O)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)CBr)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A solution of 1,4-dioxane dibromide (0.5 g, 0.002 mol) in 1,4-dioxane (10 ml) was added dropwise to a stirred solution of 2-(5-acetyl-2-ethoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 15; 0.64 g, 0.002 mol) in 1,4-dioxane (40 ml) and the resulting mixture heated under reflux for 2 hours. The precipitate which formed in the cool reaction mixture was collected by filtration, washed with 1,4-dioxane followed by diethyl ether, and air-dried to give 2-(5-bromoacetyl-2-ethoxyphenyl)-8-methylquinazolin-4(3H)-one, which was used without further purification. The crude bromoacetyl intermediate was suspended in stirred acetonitrile (40 ml) and morpholine (0.174 g, 0.002 mol) added; after 1.5 hours at room temperature, the solvent was evaporated under vacuum. The residue was suspended in water (20 ml) and the suspension extracted with dichloromethane (3×20 ml), then the extracts were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel using a methanol in dichloromethane elution gradient (0-1%) and then the product crystallized from ethyl acetate-hexane to give the title compound as a white powder (0.29 g, 36%), m.p. 172-173° C.
Reaction SMILES: [C:1]([N:9]([C:11](=[O:16])[C:12]([NH:14][NH2:15])=[O:13])[NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CC(N(C)C)=O>[C:1]([N:9]([C:11](=[O:16])[C:12]([NH:14][NH2:15])=[O:13])[NH:10][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C(=O)N(N)C(=O)c1ccccc1
Reactant: CCCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCCC(=O)NN(C(=O)C(=O)NN)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
11.1 g (0.05 mols) of N-benzoyloxalic acid dihydrazide are suspended in 250 ml of dimethylacetamide and dropwise admixed, while stirring, with 5.8 g (0.055 mols) of butyric acid chloride. The reaction mixture is stirred for 3 hours at 60°-70° C., then 500 ml of ice water are added and filtering under suction is carried out at 5°-10° C. The resultant product is recrystallised from methylcellosolve. There is obtained N-benzoyl-N'-butyroyloxalic acid dihydrazide (stabiliser 44), M.P. 254° C.
Reaction SMILES: [CH:1]1([C@H:7]([OH:20])[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:1]1([C@H:7]([O:20][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[O:19][CH:26]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](CC[C@@H](OC3CCCCO3)C3CCCCC3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of the diol 7 (6.0 g, 21.2 mmol) and dihydropyran (7.80 mL, 84.8 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. A catalytic amount of p-TsOH (0.05 g, 0.26 mmol) was added and the mixture was stirred for 30 min at 0° C. The reaction was then quenched by adding sat. aqueous NaHCO3 (10 mL). Layers were separated and the aqueous phase was extracted with 2×25 mL of CH2Cl2. Combined organic layers were dried over anhydrous K2CO3, filtered and concentrated to afford a colorless oil which was purified by passage through a short column of silica (Rf 0.46, 1:1 EtOAc/hexanes). The bis-THP ether 8 (8.59 g, 89% yield) was isolated as a colorless oil which solidified upon standing. 1H NMR (CDCl3) δ (characteristic peaks only) 5.00 (m, 1H), 4.75-4.45 (m, 2H), 3.85 (m, 2H), 3.60-3.30 (m, 4H).
Reaction SMILES: [OH-].[Na+].OO.[CH2:5]([O:8][CH2:9][CH2:10][N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21]([N:24]2[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[C:15]([CH3:33])[CH:14]=1)[CH:6]=[CH2:7].S([O-])([O-])=[O:37].[Na+].[Na+]>CO.CS(C)=O>[CH2:5]([O:8][CH2:9][CH2:10][N:11]([CH3:35])[C:12]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21]([N:24]2[CH2:25][CH2:26][C:27]([NH2:32])([C:30]([NH2:31])=[O:37])[CH2:28][CH2:29]2)(=[O:22])=[O:23])=[C:15]([CH3:33])[CH:14]=1)=[O:34])[CH:6]=[CH2:7]
Reactant: O=S([O-])[O-]
Reactant: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C#N)CC2)c(C)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 N aqueous sodium hydroxide solution (1.41 ml) and 30% aqueous hydrogen peroxide (0.95 ml) were added to a solution of the resulting N-(2-allyloxy-ethyl)-4-[2-(4-amino-4-cyano-piperidine-1-sulfonyl)-ethyl]-3,N-dimethyl-benzamide in methanol (24 ml)-DMSO (1.3 ml), and the mixture was stirred at room temperature for one hour. A 10% (w/w) aqueous sodium sulfite solution (2.64 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 40 minutes. The precipitated insoluble matter was then removed by filtration. The resulting filtrate was concentrated under reduced pressure to give 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-amino-piperidine-4-carboxylic amide (2.13 g). This was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:11]1([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=Cc1c(Cl)ncnc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.00 g, 5.65 mmol) in chloroform at 0° C. were added azetidine (99%, 0.392 mL, 5.71 mmol) and triethylamine (5 drops). The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product. Yield: 880 mg, 4.45 mmol, 79%. LCMS m/z 198.1, 200.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.34-2.43 (m, 2H), 4.12-4.33 (br m, 4H), 8.30 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([Si:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[O:45][CH:46]1[CH2:51][CH2:50][CH:49](O)[CH2:48][CH2:47]1)([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:49]3[CH2:48][CH2:47][CH:46]([O:45][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:51][CH2:50]3)=[CH:17][CH:18]=1)[CH2:8]2
Reactant: CC(C)(C)[Si](OC1CCC(O)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (4 g, 14.74 mmol) in dry THF (100 mL) and DMF (75 mL) was added triphenyl phosphine (5.8 g, 22.11 mmol) and 4-(t-butyl-diphenyl-silanyloxy)-cyclohexanol (6.27 g, 17.69 mmol). The reaction mixture was cooled to 0° C. and DEAD (3.48 mL, 22.11 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography using DCM as solvent to give 4.73 g (53%) of N-adamantan-2-yl-4-[4-(t-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C[N:22](C=O)C>>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:22])[CH:8]=[C:7]2[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2[nH]cc(CCc3cccnc3)c2c1
Agent: [H-]
Agent: [Na+]
Product: Nn1cc(CCc2cccnc2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (600 mg, 15 mmol, 60% in mineral oil) in DMF (10 mL) at 0° C. is treated with 5-fluoro-3-(2-pyridin-3-yl-ethyl)-1H-indole (240 mg, 1 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (565 mg, 5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×1050 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(F)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Yield: 60.3 %

Procedure:
A mixture of ethyl 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (3.6 g) and potassium hydroxide (2 g) in methanol (50 ml) was refluxed for 30 minutes. The solvent was evaporated. The residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated. The residue obtained was recrystallized from ethanol to give crystals of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (2 g).
Reaction SMILES: [Br-].[C:2]([CH:4](C)[CH2:5]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[Na].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([O:41][C:42]([NH:44][C:45]([CH3:52])([CH:50]=O)[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([NH:44][C:45]([CH3:52])(/[CH:50]=[CH:5]\[CH2:4][C:2]#[N:3])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C#N)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)C(C)(/C=C\CC#N)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
3-Cyanobutyltriphenylphosphonium bromide (0.990 g, 0.0025 mol) is taken up in dry THF (30 mL) and purged with argon. To this sodium is added bis(trimethylsilyl)amide (3 mL 1.0M solution in THF, 0.003 mol) at 20° C. to 25° C. and the reaction mixture is stirred at this temperature for 10 min. After a yellow color change is observed, a solution of the methyl 2-[(tert-butoxycarbonyl)amino]-2-methyl-3-oxopropanoate product of Example 1c (578 mg, 0.0025 mol) in THF (20 mL) is then added and the reaction mixture is stirred under argon for 8 h at 25° C. It is then concentrated on rotovap and the residual mass is taken up in EtOAc (100 mL) and washed with DI water (20 mL). The organic layer is dried over anhydrous MgSO4, decolorized with activated charcoal (1.0 g), filtered through Celite and concentrated on a rotovap to give crude reaction product as a dark brown oil. Column chromatography of this crude product affords the desired title product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][N:19]=1>>[C:23]1([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccccc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole: MS (ES) m/z 369 (M+1).