Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([NH2:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:32][CH2:31][O:30][C:28]([N:15]1[C:16]([NH2:17])=[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][C:11]2=[N:14]1)=[O:29]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(N)c2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 94.1 g of 3-amino-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 1.7 L of THF were added 135 mL of N,N-diisopropylethylamine. A solution of 37.6 mL of ethyl chloroformate in 300 mL of THF was added dropwise at 0° C. during 75 min. The mixture was stirred at 0° C. for 30 min. then evaporated under vacuum. The residue was taken-up with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with 500 mL brine, dried over sodium sulfate, and evaporated to dryness. The crude mixture of isomers was purified by silica gel flash-chromatography, using a starting 87:13 mixture of dichloromethane-ethyl acetate as eluant, and increasing gradually the percentage of ethyl acetate up to 50%. The fractions containing the same isomer were evaporated to give 61.6 g of 3-amino-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester.
Reaction SMILES: C(O[C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:21]([O:23][C:24](=[O:36])[CH:25](C(OCC)=O)[C:26](OCC)=[O:27])[CH3:22]>>[CH2:21]([O:23][C:24]([C:25]1[C:6](=[O:20])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:26]=1[OH:27])=[O:36])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O

Procedure:
A mixture of benzyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.28 g, 4.70 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 mL) in a test tube was heated in an oil bath (bath temperature: 220° C. to 230° C.) for 10 min; TLC (EtOAc/hexanes:1/1 by volume) showed good conversion; then cooled, the reaction mixture was directly purified with silica gel column to give the desired product as brown solid (1.00 g). ESI (m/z): 313 (M+H)+.
Reaction SMILES: C[O-].[Na+].[NH2:4][C@H:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8].[O:16]1[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17]1.Cl>CO>[OH:16][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][NH:4][C@H:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: CCCCCCCCCCC1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCC(O)CN[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.9 %

Procedure:
27.01 g of sodium methoxide and 82.6 g of (S)-3-amino-3-phenylpropionic acid were dissolved in 800 ml of methanol. After adding 92 g of 1,2-epoxydodecane, the solution was stirred at room temperature for 20 h. Subsequently, the pH of the solution was adjusted to pH 6 with methanolic hydrochloric acid and the sodium chloride which crystallized out filtered off. After the methanol was distilled off, an oily residue remained, which crystallized in the course of stirring with 700 ml of acetone. This resulted in 153.4 g of colorless crystals. 1H NMR (DMSO) δ (ppm): 0.85 (t, 3H), 1.13-1.31 (m, 18H), 2.28/2.60/2.70/2.86 (m, 2H), 3.02 (m, 1H), 3.34 (m, 1H), 3.66-3.78 (m, 1H), 4.57 (m, 1H), 5.20/5.29 (s, br., 1H, OH), 7.42 (m, 3H), 7.60 (m, 2H), 9.40 (s, br., 2H, NH2+), 12.56 (s, 1H, CO2H)
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[C:29]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ccc(OCc2cccc(CC(=O)O)c2)cc1

Procedure:
{3-[4-(2-Methoxy-pyridin-3-yl)-phenoxymethyl]-phenyl}-acetic acid was prepared using general procedure 4 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 2-methoxy-pyridine-3-boronic acid (available from Lan-caster Synthesis Ltd., Lancashire, UK). Mass spectrum MH+=350.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:19]([NH:26][C:27]([S:29][CH3:30])=[NH:28])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:28]=[C:27]([S:29][CH3:30])[NH:26][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid (3.2 g, 10.4 mmol), methyl N-Boc-carbamimidothioate (4.7 g, 12.4 mmol), HATU (5.0 g, 26.0 mmol) and DIPEA (6.7 g, 52.1 mmol) were dissolved in DCM (200 mL). After the resulting mixture was stirred at room temperature for 2 h, the reaction mixture was concentrated and methanol (50 mL) was added and filtered. The solid was collected to give methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate (3.0 g, 60%). 1H NMR (DMSO, 400 MHz) δ 12.84 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.32-7.27 (m, 2H), 5.72 (s, 1H), 4.49 (s, 4H), 2.30 (s, 3H), 1.49 (s, 9H)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5](=O)[NH:4][C:3]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18].P(Cl)(Cl)([Cl:26])=O>CCCCCCC.C(OCC)(=O)C>[Cl:26][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(OC(C)C)cc2c1O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O

Procedure:
2.0 g of compound B from Example 1e) were reacted with phosphorus oxychloride analogously to 1f). After chromatography using heptane/ethyl acetate (4:1) on silica gel, 1.5 g of product were isolated; m.p. 116-118° C. (from petroleum ether).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:34]([C:29]3[N:30]=[C:31]([CH3:33])[O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:37])([F:19])[F:38])[CH:23]=3)=[O:35])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(3-Iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 55) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (136 mg, 78%);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl-:12].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:12])[CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
2-Nitroanisole (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 4 h. The product was purified by column chromatography to give 2-nitro-4-chloroanosole (55%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:29](=[O:31])[CH3:30])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) in THF (4 mL) was added triethylamine (65 mg, 90 μL, 0.64 mmol) and the resulting mixture cooled to 0° C. with ice. Then a solution of acetyl chloride (50 mg, 50 μL) in THF (1 mL) was added and the resulting mixture allowed to warm up to room temperature over 1 h. The mixture was then filtered and the filtrate evaporated before being diluted with methanol and potassium carbonate (10 mg) added. After one hour at room temperature the mixture was extracted with dichloromethane. The combined organic layers were then washed with water and then dried over sodium sulfate, filtered and evaporated to afford the title compound (145 mg, 84%) which was obtained as white crystals. MS: m/e=324.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:20])([F:32])[F:33])(=[O:30])=[O:29])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: O=C1C(Cl)=C(N2CCNCC2)C(=O)c2ccccc21
Product: O=C1C(Cl)=C(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)C(=O)c2ccccc21

Procedure:
A 1.5 g portion of 3-chloro-2-piperazinyl-1,4-naphthoquinone and 1.26 g of 2-trifluoromethylbenzenesulfonyl chloride were reacted as described in Example 56, giving 1.53 g of the desired product, mp 122°-124° C.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH2:43][CH2:42][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([O:33]C(C)(C)C)=[O:32])[C:17]3=[O:41])[CH2:15][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl>O1CCOCC1>[N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([OH:33])=[O:32])[C:17]3=[O:41])[CH2:42][CH2:43]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4nnc5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4nnc5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-((8-(3-(1H-benzo[d][1,2,3]triazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.21 g, 0.34 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.2 g, 99%); 1H NMR (DMSO-d6): δ 1.89 (d, 2H, J=14.8 Hz), 2.49-2.51 (m, 2H), 2.95-3.03 (m, 2H), 3.22-3.27 (m, 2H), 3.53-3.69 (m, 4H), 4.64 (d, 4H, J=4 Hz), 4.86 (t, 2H, J=7.2 Hz), 6.78 (t, 1H, J=7.2 Hz), 7.04 (d, 2H, J=8 Hz), 7.20 (t, 2H, J=7.2 Hz), 7.41-7.61 (m, 4H), 7.86-7.89 (m, 2H), 7.97 (d, 1H, J=8.4 Hz), 8.07 (d, 1H, J=8.8 Hz), 10.94 (br, 1H), 13.03 (br, 1H); MS for C30H32N6O3 m/z 525.08 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: OCc1ccncc1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(2,4-dimethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (33 mg, 0.099 mmol), pyridine-4ylmethanol (2.52 mg, 0.148 mmol), triphenylphosphine (39 mg, 0.149 mmol) were pre-weighed into a 4 mL glass vial. Tetrahydrofuran (THF) (0.6 mL) was added followed by diisopropyl diazene-1,2-dicarboxylate (DIAD) (0.029 mL, 0.148 mmol). The vial was capped and stirred at RT for 2 days. The reaction mixture was filtered to remove any insoluble materials. The sample was purified by mass directed autoprep on an Xbridge column using acetonitrile:water with an ammonium carbonate modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH2:19][Cl:20])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].O.Cl>CO>[Cl:20][CH2:19][CH:17]([OH:18])[C:15]1[O:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C(CCl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(C(O)CCl)o2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
Sodium borohydride (1.6 g, 0.043 mole) was added in portions to a stirred mixture of 11.5 g (0.043 mole) of chloromethyl 5-(p-nitrophenyl)-2-furyl ketone in 150 ml of absolute methanol over 10 minutes at 15°-20°. The resulting solution was stirred at ambient temperature for 2.5 hours, poured into a mixture of ice and water (400 ml), and made acidic with 5% aqueous HCl. The yellow solid was collected by filtration and washed with water to give 11.5 g (100%) of title compound. Recrystallization from a MeOH--H2O mixture gave an analytical sample, m.p. 111°-113°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:4]3[CH:5]=[CH:6][N+:1]([O-:28])=[CH:2][CH:3]=3)=[N:11][C:10]=2[CH:12]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)cc1
Yield: 78.2 %

Procedure:
To a mixture of 0.47 g of 2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.64 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred while ice-cooling for 30 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with chloroform, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution. Organic layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 0.39 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 14”).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][P:23]([CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH:4]=1)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine (4.88 g, 17.0 mmol) from Step 2 was treated neat with triethylphosphite (4.36 mL, 25.4 mmol) and heated to 150° C. After 6 h, the reaction mixture was cooled, treated with an additional 0.5 mL triethylphosphite (2.9 mmol) and reheated to 150° C. After 6 h, the reaction mixture was removed from the heat and slowly treated with heptane (about 60 mL) while stirring to afford a white solid. The solid was collected by filtration, washed with heptane and dried in a vacuum oven for 16 h at 45° C. to afford a white powder (5.99 g, 91% yield). MS (APCI) M+1=390.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.02 Hz, 6H) 3.18 (d, J=21.83 Hz, 2H) 3.99-4.10 (m, 4H) 7.01 (d, J=8.58 Hz, 1H) 7.03-7.08 (m, 1H) 7.12 (q, J=2.21 Hz, 1H) 7.19-7.24 (m, 1H) 7.38 (t, J=7.90 Hz, 1H) 7.90 (dd, J=8.58, 2.53 Hz, 1H) 8.43 (dd, J=1.66, 0.88 Hz, 1H).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:35]3[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1cccnc1)c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cccnc3)c3ccc(Cl)c(Cl)c3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (78.6 mg, 0.183 mmol, Intermediate 16) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (3,4-dichlorophenyl)(pyridin-3-yl)methanone (50.2 mg, 0.199 mmol, Intermediate 30: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 20 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (d, J=2.0 Hz, 1H), 8.32 (dd, J=4.8, 1.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.5, 0.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 2H), 7.53-7.48 (m, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.17 (dd, J=7.8, 4.7 Hz, 1H), 7.06 (dd, J=8.4, 2.2 Hz, 1H), 6.39 (dd, J=2.4, 1.9 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 3H); MS m/e 601.1 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.S([CH2:20][N+:21]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[C:20]([CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[N:21]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CN2CCC1CC2
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A mixture of 3-quinuclidinone (12.5 g; 0.10 moles), tosylmethyl isocyanide (25.4 g; 0.13 moles) and dry ethanol (10 ml; 0.17 moles) in dry dimethoxyethane (350 ml) was cooled in ice and treated portionwise with potassium t-butoxide (28.0 g; 0.25 moles) while maintaining the temperature between 5° C. and 10° C. After addition was complete the ice bath was removed and stirring was continued for a further 30 min. The reaction was then heated at 4° C. for 2.5 h. After cooling, the precipitate was filtered off and the filtrate concentrated in vacuo. Purification on neutral alumina (Brockmann grade 1) using 2% methanol in ethyl acetate as eluant afforded the title compound as a syrup (10.0 g: 74%) which crystallised on cooling.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([N:20]([CH2:31][CH3:32])C(=O)OCC3C=CC=CC=3)[N:19]=[C:6]2[N:5]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[C:4]=1[CH3:43])#[N:2]>CO.[Pd]>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C@H:8]2[N:7]3[N:17]=[C:18]([NH:20][CH2:31][CH3:32])[N:19]=[C:6]3[N:5]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=3)[C:4]([CH3:43])=[C:3]2[C:1]#[N:2])=[CH:14][CH:13]=1)#[N:16]
Reactant: CCN(C(=O)OCc1ccccc1)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCNc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(ethyl)carbamate (17.0 mg, 29 μmol) was dissolved in degassed methanol (2 ml). After addition of palladium on activated carbon (10%; 2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 1 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.9 mg, 83% of theory).