Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]\[O:8][CH2:9][CH3:10])CCC.Br[C:20]1[C:21]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1>CC#N.[N+](CC)(CC)(CC)CC.[Cl-].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>[Cl:26][C:23]1[N:22]=[C:21]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:20](/[CH:6]=[CH:7]\[O:8][CH2:9][CH3:10])=[CH:25][N:24]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CCO/C=C\c1cnc(Cl)nc1NC(CC)CC
Temperature: 100 °C

Procedure:
To a solution of tributyl-((Z)-2-ethoxy-vinyl)-stannane (4.25 g, 8.8 mmol) in CH3CN (10 mL) is added (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (2.25 g, 8 mmol), Et4NCl (1.33 g, 8 mmol) and Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) at ambient temperature. The reaction mixture is purged with N2, sealed in a microwave reactor and heated at 100° C. for 20 min. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is purified by flash chromatography (SiO2, EtOAc/hexane 5:95 to 40:60) to give [2-Chloro-5-((Z)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[CH2:11]([O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[Br:25])[CH:12]=[CH2:13].[C:26](#[N:30])[CH2:27][C:28]#[N:29].N1CCCCC1>C(O)C.O>[CH2:11]([O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18]([CH:19]2[C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[O:10][C:26]([NH2:30])=[C:27]2[C:28]#[N:29])=[CH:17][C:16]=1[Br:25])[CH:12]=[CH2:13]
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Reactant: Oc1ccc2c(c1)OCO2
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: C=CCOc1c(Br)cc(C2C(C#N)=C(N)Oc3cc4c(cc32)OCO4)cc1OC
Temperature: 80 °C

Procedure:
3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (200 mg, 0.44 mmol, 44%).
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:3])[CH3:4]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(C/C=C\CCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
The compound (12-9) (1.39 g) was subjected to catalytic reduction in ethyl acetate (15 ml) using 5% Pd-C (0.14 g) under hydrogen atmosphere. The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=8/2) to give the titled compound (12-10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.O=[C:18]1[CH2:24][N:23]([CH2:25][CH2:26][CH2:27][CH:28]=O)[CH2:22][CH2:21][CH2:20][O:19]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:41])C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:28][CH2:27][CH2:26][CH2:25][N:23]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18][C:24]3=[O:41])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CCCCN1CCCOC(=O)C1
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCCCN1CCCOCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca.13 mg 50 μumole) as described in Example 1, was added 440 μL solution of 4-(2-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2 dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 M slurry of sodium triacetoxyborohydride in 1,2 dichloroethane. The reaction was shaken at room temperature for 48 h. After quenching with 2 mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL water and ethyl acetate to workup flasks. The organic phase was washed, dried and concentrated. Purification by chromatography yielded 4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one 17, MS: 389([M+H]+);
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH:6][CH2:12][CH2:11][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CCNc1c(F)cc(Cl)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.5 g, 1.8 mmol), vinylmethylsulfone (0.2 g, 1.8 mmol), Cs2CO3 (1.17 g, 3.6 mmol) and DMF (15 mL) was heated with stirring at 50° C. overnight. The resulting mixture was poured into water and then extracted with EA (50 mL×3). The combined organic phases were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (EtOAc:PE=1:40) to give 4-chloro-2-fluoro-6-iodo-N-[2-(methylsulfonyl)ethyl]aniline (0.42 g, yield: 61%).
Reaction SMILES: Cl.Cl.NC1C(N)=CN=C([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)N=1.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([N+:32]([O-:34])=[O:33])=[C:27]([CH3:35])[CH:26]=1.N1CCC[C@@H](C(N2CCCC2)=O)C1>>[NH2:31][C:29]1[N:30]=[C:25]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:18])[CH2:12]2)[CH:26]=[C:27]([CH3:35])[C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1cc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: O=C([C@@H]1CCCNC1)N1CCCC1
Product: Cc1cc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc(N)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
(R)-(1-(6-Amino-4-methyl-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone was prepared using a method analogous to the one used for Intermediate 2, Step 1 but using 6-chloro-4-methyl-3-nitropyridin-2-amine and (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone as starting materials. The reaction mixture was run at 70° C. for 1 h. MS (ES+APCI) (M+H) 333.9; LCMS retention time 4.322 min (Method Z).
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:4]=1.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[N:23]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[O:20][CH2:19][CH2:18][N:17]([C:22]4[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][N:31]=5)[N:23]=4)[CH2:16][CH2:15]3)=[CH:12][CH:13]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc(C3CCNCCO3)cc2)no1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)no1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a slurry of optically active 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-[1,4]oxazepane hydrochloride (0.12 g, 0.41 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.09 g, 0.38 mmol) was added triethylamine (0.21 mL, 1.5 mmol) at room temperature. The mixture was stirred for 20 hours and poured into water. Extractive workup with chloroform was performed and the organic phase was dried over sodium sulfate. Concentration followed by purification of the residue by flash column chromatography on silica gel (chloroform/methanol=100/0 to 90/10 as eluants) yielded (+)-2-{7-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A100) (0.09 g, 0.19 mmol, 50%) as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C[O:11][CH:12](OC)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C(O)C.N>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: COC(CCCCCO)OC
Reactant: CNc1ccncc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCO
Solvent: O
Product: Cn1c(CCCCCO)nc2cnccc21
Yield: 30.1 %

Procedure:
3-Amino-4-(methylamino) pyridine (1.23 g), 6,6-dimethoxyhexanol (1.62 g), copper (II) acetate monohydrate (4 g), ethanol (30 ml) and water (30 ml) were mixed and then heated at 150° in a sealed tube for 3 hours. To the cold reaction mixture was added concentrated aqueous ammonia (5 cm3) and the mixture was then filtered through "Hyflo" (Trade Mark), diluted with water (50 ml) and extracted with methylene chloride (3×200 ml). The combined organic extracts were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol. The fractions containing the product were evaporated to leave the title compound, (0.66 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[CH2:21](N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[CH2:30][N:31](CC)CC>CN1C(=O)CCC1.O>[CH:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([NH:31][CH2:30][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:3]([NH2:20])=[N:4][CH:5]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])([CH3:19])[CH3:18]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(NCCc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 40.1 %

Procedure:
A mixture of 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (50 mg, 0.1404 mmol), benzylamine (30.09 mg, 30.67 μL, 0.2808 mmol) and Et3N (28.41 mg, 39.13 μL, 0.2808 mmol) in NMP (500 μL) were heated at 120° C. under microwave conditions for 1.5 hours. A further portion of benzylamine (225.7 mg, 230.1 μL, 2.106 mmol) was added and the reaction heated at 120° C. under microwave conditions for a further 45 minutes. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a cream solid (22.3 mg, 42% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.16 (d, 6H), 3.41 (sept, 1H), 4.70 (d, 2H), 7.15 (br s, 1H), 7.26 (t, 1H), 7.36 (t, 2H), 7.44 (d, 2H), 7.82 (d, 2H), 7.96 (s, 1H) and 8.14 (d, 2H) ppm; MS (ES+) 383.2.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:11]=[C:12]([OH:20])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:20][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)c2ccccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(OP(=O)(Cl)Cl)c2ccccc2c1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.143 mL, 1 equiv) and 3-tert-butylnaphthalen-1-ol (J. Org. Chem. 1995, 60, 2909-2911, 0.308 g, 1 equiv), were stirred in anhydrous diethyl ether (8 mL). Anhydrous triethylamine was added (0.214 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate is very unstable at room temperature. The reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[N:5]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)=[N:5]2
Reactant: Nc1ccc(Oc2ccc3nccn3n2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Oc2ccc3nccn3n2)cc1)c1ccccc1
Yield: 88 %

Procedure:
Using 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol), N-methylpyrrolidone (1 mL) and benzoyl chloride (0.116 mL, 1.00 mmol), and in the same manner as in Example 145, the title compound (144 mg, 0.44 mmol, yield 87%) was obtained.
Reaction SMILES: [Br:1][C:2]1C=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@H:8]2[OH:12])=[CH:4][CH:3]=1.BrC1[N:21]=CC(O)=CC=1>>[Br:1][C:2]1[N:21]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@H:8]2[OH:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Product: O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 1 was prepared according to the general procedure for the synthesis of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol in Example 2, except that 6-bromopyridin-3-ol was used in place of 4-bromophenol, and the crude product was purified by silica gel chromatography (Gradient: 20% to 70% ethyl acetate in heptane). Yield: 5.24 g, 20.2 mmol, 61%. 1H NMR (500 MHz, CDCl3) δ 3.79 (dd, J=9.9, 1.9 Hz, 1H), 3.87 (dd, J=10.4, 1.8 Hz, 1H), 4.00 (dd, J=9.9, 4.3 Hz, 1H), 4.19 (dd, J=10.4, 4.7 Hz, 1H), 4.38 (br m, 1H), 4.59 (br s, 1H), 4.68 (br d, J=4.4 Hz, 1H), 7.14 (dd, J=8.7, 3.2 Hz, 1H), 7.32 (dd, J=8.7, 0.5 Hz, 1H), 8.01 (br d, J=3.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=1[CH3:28].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:28][C:18]1[CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 18 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Trifluoromethane sulfonic anhydride (0.217 mL, 1.32 mmol) was added dropwise to methyl 2-(4-hydroxy-3-methylphenyl)acetate (159 mg, 0.88 mmol), in DCM (4 mL) at 0° C. under nitrogen. The resulting solution was then treated with triethylamine (0.369 mL, 2.65 mmol) and allowed to warm to and stir at 18° C. for 16 hours. The mixture was diluted with DCM (20 mL) and water (20 mL) and the organics separated. The organics were washed with saturated NaHCO3 (aq, 50 mL), brine (10 mL) dried (MgSO4) and evaporated to crude material. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-methyl-4-(trifluoromethylsulfonyloxy)phenyl)acetate (169 mg, 61.3%) as a colourless oil.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([NH:21][C:11](=[O:13])[C:10]2[CH:14]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: N#Cc1ccc(NC(=O)c2cnc(OCC(F)(F)F)c(C3CCCC3)c2)cc1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 4-aminobenzonitrile (CAN 873-74-5, 49.0 mg, 0.41 mmol) as starting materials; off white solid (10 mg, 7.4%). MS (ESI): 388.2 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[CH:10]=[O:11].[C:19]([O:22]C(=O)C)(=O)[CH3:20]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:9]([CH:10]([O:11][C:19](=[O:22])[CH3:20])[C:1]#[N:2])[CH:8]=[C:7]([O:6][CH3:5])[C:14]=1[O:15][CH3:16]
Reactant: [C-]#N
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C#N)OC(C)=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of potassium cyanide (41.5 g), triethylbenzylammonium chloride (5.23 g), water (130 ml) and dichloromethane (150 ml) was cooled to 0° C. To the vigorously stirred mixture, a solution containing the 3,4,5-trimethoxy-benzaldehyde (100.0 g) and acetic anhydride (52.1 g) in dichloromethane (150 ml) was added drop wise at 0° C. during 30 minutes. The stirring was continued at 0° C. for 30 minutes and then at ambient temperature for one hour. The organic phase was separated, dried and concentrated to dryness, leaving crude 3,4,5-trimethoxyphenyl-α-acetoxyacetonitrile. Crystallization from ethanol-water afforded the pure product (104 g), m.p. 65-66° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[SH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[F:1][C:2]1[C:7]([C:8](=[O:9])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Following the general procedure described above, reaction of pentafluorobenzoyl chloride (6.92 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (7.97 g, 87%): mp 51° C.; 1H NMR δ 7.37-7.42 (m, 1H), 7.75-7.79 (m, 1H), 7.81-7.87 (m, 1H), 8.67-8.71 (m, 1H); Anal. Calcd for C12H4NOS: C, 47.22; H, 1.32; N, 4.59. Found: C, 47.59; H, 1.29; N, 4.38.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:37])[C:9]1=[O:38])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:38])[N:10]([CH3:37])[C:11]=3[CH:17]=[C:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1cc(-c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (30 mg, 0.054 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (4.58 mg, 0.109 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4 (3H,5H)-dione (4 mg, 14.4% yield) as a white solid. 1H NMR (CDCl3) δ: 7.47 (t, J=8.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.26-7.24 (m, 1H), 7.20 (d, J=8.3 Hz, 3H), 6.81 (d, J=8.4 Hz, 2H), 6.10 (s, 1H), 5.59 (s, 2H), 4.26-4.13 (m, 2H), 3.56 (d, J=6.7 Hz, 1H), 3.50 (d, J=9.8 Hz, 5H), 1.90 (d, J=5.4 Hz, 2H). LCMS: MH+ 508 and TR=3.007 min.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[F:6][CH:7]([F:17])[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#N)=[CH:11][CH:10]=1.Cl.C([O:21]CC)C>O1CCCC1>[F:6][CH:7]([F:17])[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([CH:2]2[CH2:4][CH2:3]2)=[O:21])=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: BrC1CC1
Reactant: N#Cc1ccc(OC(F)F)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Upon a dry argon atmosphere, a mixture of 1.6 g (0.066 mole) of magnesium, 7.9 g (0.066 mole) of cyclopropylbromide, 60 ml of anhydrous diethyl ether, and 60 ml of anhydrous tetrahydrofuran was heated at reflux for 2.5 hours. The stirred mixture was cooled to room temperature, and a solution of 11.1 g (0.066 mole) of (4-difluoromethoxybenzonitrile) in 40 ml of anhydrous diethyl ether and 40 ml of anhydrous tetrahydrofuran was added during one hour. After complete addition, the mixture was heated at reflux for two hours, then stirred at room temperature for approximately 18 hours. A 100 ml portion of 2 N hydrochloric acid was added slowly to the mixture, and the whole was stirred for one hour. The mixture was extracted with three 100 ml portions of diethyl ether. The ether extracts were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give an oil. The oil was subjected to column chromatography on silica gel, eluting with toluene/ethyl acetate (95:5), to give 8.3 g of (4-difluoromethoxyphenyl)(cyclopropyl) ketone.