Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.[N:41]1[CH:46]=[CH:45][N:44]=[C:43]2[NH:47][C:48]([C:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[N:52]([CH2:59][CH2:60][CH2:61]O)[CH:51]=3)=[CH:49][C:42]=12>O1CCCC1>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH2:61][CH2:60][CH2:59][N:52]2[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:50]([C:48]3[NH:47][C:43]4=[N:44][CH:45]=[CH:46][N:41]=[C:42]4[CH:49]=3)=[CH:51]2)[CH:36]=1
Reactant: Oc1cccnc1
Reactant: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(OCCCn2cc(-c3cc4nccnc4[nH]3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.6 %

Procedure:
A solution of diisopropylazodicarboxylate (269 μM) in tetrahydrofuran (0.5 mL) was added dropwise, over 2 minutes, to a solution of triphenylphosphine (359 mg) in tetrahydrofuran (2.5 mL) at 0° C. under an atmosphere of nitrogen. After stirring at that temperature for 20 minutes the mixture was treated with a solution of 3-hydroxypyridine (65 mg) in tetrahydrofuran (1 mL) over 1 minute then with a suspension of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol [200 mg, Example 2(a)] in tetrahydrofuran (2 mL). The mixture was allowed to warm to ambient temperature over 18 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and methanol (9:1, v/v) to give the title compound (110 mg) as a yellow solid, m.p. 208-209° C. MS: 370 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:30])(=[O:29])[C:14]=2[CH:31]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:29])(=[O:30])[C:14]=2[CH:31]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Pyrrolidine (0.14 mL, 1.74 mmol) was added to a solution of Example 56k (0.5 g, 1.16 mmol) in dry DMF (5 mL) in an atmosphere of nitrogen. It was stirred at 100° C. for 5 h. The reaction mixture was concentrated and treated with chilled water to obtain a solid which was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.375 g, (69.44%); 1H NMR (DMSO-d6): δ 1.75 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.85 (m, 2H, CH2), 3.20 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.25 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.20 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (ES−) 463 (M+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][CH:37]=1.[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:42]([C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccncc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccncc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 4-pyridine carboaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16][S:17][CH:18](SC)[CH2:19][N+:20]([O-:22])=[O:21].O.O.C(O)(=O)C(O)=O>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([S:17][CH3:16])=[CH:19][N+:20]([O-:22])=[O:21])[CH:7]=1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSC(C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN(C)C)c1
Yield: 64 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (10 g) and 1,1-bis-(methylthio)-2-nitroethane (16 g) were heated under reflux in tetrahydrofuran for 19 hours. Oxalic acid dihydrate (1.3 g) was added and the resulting precipitate was discarded. The solvent was removed to leave the title compound as a crystalline solid (10 g) m.p. 59°-63°.
Reaction SMILES: [C:1]([N:4]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[N:12](C(OCC)=O)[C:11]=1[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:5][C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2]>ClCCl>[C:1]([N:4]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N(CC(=O)OC)C(C)=O)c2ccc(Cl)cc21
Solvent: ClCCl
Product: CC(=O)N(CC(=O)O)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-(N-acetyl-N-methoxycarbonylmethylamino)-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (step 1). m.p.: 148-154° C. (dichloromethane) 1H-NMR (DMSO-d6) δ: 12.53 (1H, br s), 12.17 (1H, br s), 7.85 (1H, d, J=8.8 Hz), 7.78-7.62 (3H, m), 7.62-7.51 (3H, m), 7.22 (1H, dd, J=1.8, 8.8 Hz), 3.96 (1H, d, J=17.2 Hz), 3.66 (1H, d, J=17.2 Hz), 1.80 (s, 3H)
Reaction SMILES: FC1C=CC([N+]([O-])=O)=C(C=1)N.[CH3:12][C@H:13]1[NH:18][CH2:17][C@@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1C(=O)CCC1>C(Cl)Cl>[CH3:22][N:20]([CH2:19][C@@H:16]1[O:15][CH2:14][C@@H:13]([CH3:12])[NH:18][CH2:17]1)[CH3:21]
Reactant: C[C@@H]1CO[C@H](CN(C)C)CN1
Agent: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@@H](CN(C)C)CN1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2S,5R)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and NMP was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (2×) and dried (Na2SO4). Purification via chromatography on silicagel (10% MeOH in dichloromethane), afforded the desired product as a dark yellow foam. LC/MS m/z 295.2 (MH+) Rt 1.86 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][S-:12].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(F)ccc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(SC)ccc1Br
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at room temperature for 30 minutes and at 85° C. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)[CH:20]=1.C(N(CC)CC)C>C(O)CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[N:23]=2)[CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)nc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Clc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1

Procedure:
Following the general procedure of Example 33, Step 2, and making non-critical variations, 1-(5-chloropyridin-2-yl)piperazine (0.424 g), 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.517 g), triethylamine (0.282 g), and ethylene glycol (2 mL) give, after crystallization from dichloromethane/ethyl ether, 0.621 g of the title compound; mp 137-138° C.; MS m/z 361, 363; IR 1593, 1480, 1245, 1324, 801, 1304 cm-1 ; 1H NMR (CDCl3) δ2.67, 3.55, 3.75, 6.57, 7.13, 7.41, 7.52, 7.53, 8.10, 8.14.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Reactant: CN=C=S
Product: CNC(=S)NC1=NN(c2ccc(Cl)cc2)CC1

Procedure:
3-Amino-1-(4-chlorophenyl)-2-pyrazoline (1.5 g) (prepared in Reference Example 6 of our European patent specification No. 22-578) and methylisothiocyanate (1.02 g) were heated together at 100° for two hours. The crude product was ground under methanol, collected by filtration, and recrystallised from acetone to yield 3-(3-methylthioureido)-1-(4-chlorophenyl)-2-pyrazoline, m.p. 237°.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH2:11]O)=[N:9][CH:10]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.CCCCCCCCCCCCN>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH2:11][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])=[N:9][CH:10]=1
Reactant: Cc1cc(CO)ncc1OCC(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCCCCCCCCCN
Product: Cc1cc(CN2C(=O)c3ccccc3C2=O)ncc1OCC(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (720 mg, white solid) from (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol (594 mg, 2.92 mmol, Step-3) and phthalimide (473 mg, 3.22 mmol) in a similar manner to Step-4 of Amine-12.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=1.CN1CCOCC1.[OH-].[Na+].Cl>C(Cl)Cl>[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH:12][C:1](=[O:3])[CH3:2])[NH:9][N:8]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
Acetyl chloride (7.7 ml, 108 mmol) was added over a period of 45 minutes to a solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (6.5 g, 43 mmol) and N-methylmorpholine (12.3 ml, 112 mmol) in CH2Cl2 (160 ml) with cooling in an ice bath. The reaction was allowed to warm to room temperature and stirred for 16 h, the solvent was removed in vacuo and the residue dissolved in methanol (150 ml). The solution was cooled in an ice bath and 25% aqueous NaOH (7.3 ml, 65 mmol) was added. After 3.25 h, 25% aqueous NaOH (0.5 ml, 4.4 mmol) was added and the reaction stirred for an additional 1.5 h. 2N HCl (20 ml) was added and the organic solvents were removed in vacuo at below 35° C. Water was added and the crude then extracted EtOAc (×2) and the extracts dried (MgSO4) and concentrated in vacuo. The resultant residue was suspended in CH2Cl2 (20 ml) with stirring. The solid was filtered and washed with CH2Cl2 (2×3 ml) and dried in vacuo to provide the title compound as a white solid (7.3 g) which was used in the subsequent step.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@@H](C(F)(F)F)CC3)C=2)C=1)(C)CO.[CH3:27][C@@:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([C:55]([F:58])([F:57])[F:56])[CH2:51][CH2:50]4)[C:40]=3[C:44]([F:47])([F:46])[F:45])[CH:35]=2)[CH2:32][O:31]C(=O)[NH:29]1>>[NH2:29][C@@:28]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:48][C@H:49]3[CH2:54][CH2:53][C@H:52]([C:55]([F:56])([F:57])[F:58])[CH2:51][CH2:50]3)[C:40]=2[C:44]([F:46])([F:47])[F:45])[CH:35]=1)([CH3:27])[CH2:32][OH:31]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Agent: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1

Procedure:
(R)-2-Amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol was synthesized as per (R)-2-Amino-2-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol (Example 259) in 75% yield, using (R)-4-Methyl-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one as starting material. MS: m/z=458.20 [M+Na]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.15 (dd, J=9.4, 1.6 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.73 (dd, J=9.3, 2.3 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 4.48-4.61 (m, 1H), 3.75 (d, J=11.0 Hz, 1H), 3.67-3.73 (m, 1H), 2.16-2.34 (m, 3H), 2.01-2.13 (m, 2H), 1.45-1.71 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.N([O-])=O.[Na+].[N+:15](=[C:17]1[N:21]=[C:20]([C:22]#[N:23])[C:19]([C:24]#[N:25])=[N:18]1)=[N-].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O>[N:15]([C:17]1[NH:18][C:19]([C:24]#[N:25])=[C:20]([C:22]#[N:23])[N:21]=1)=[N:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: N#CC1=NC(=[N+]=[N-])N=C1C#N
Reactant: N#Cc1nc(N)[nH]c1C#N
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1nc(N=Nc2nc(C#N)c(C#N)[nH]2)[nH]c1C#N

Procedure:
5.34 g (40 mmol) of 2-amino-4,5-dicyanoimidazole was dissolved in 130 ml water plus 30 ml conc. hyrdrochloric acid and diazotized by the slow addition (over 5 min) of a solution of 4.0 g of sodium nitrite in 15 ml of water. The mixture was then stirred and cooled to 0°-10° for 45 minutes. The resulting cold suspension of 2-diazo-4,5-dicyanoimidazole was poured into a stirred solution of 12.4 g of sodium sulfite and 2.2 g of sodium hydroxide in 50 ml of water at 0°. An immediate yellow precipitate formed. The mixture was stirred at 0° for 30 minutes and then the yellow solid was filtered and air dried. This gave 0.85 g of 2,2'-azobis(4,5-imidazoledicarbonitrile). Recrystallization from water gave golden plates. UV(CH3CN): 390 nm, k 90.0; sh 375 nm, k 83.4; 237 nm, k 41.3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])(C)(C)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of tert-butyllithium solution [cf. also trifluoroacylation: H. K. Nair, D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993); G. J. Pork et al., J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C. for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:13]([CH3:17])([C:15]#[CH:16])C.[F-].Cl.[CH2:21](N(CC)C1C=CC=CC=1)C>>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]2[C:5]=1[O:12][C:13]([CH:15]([CH3:16])[CH3:21])=[CH:17]2
Reactant: C#CC(C)(C)Oc1cc(C=O)ccc1OC(F)F
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Agent: [F-]
Product: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1

Procedure:
5.5 g of 4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy)benzaldehyde are refluxed with 7.2 g of cesitum fluoride for 12 h with nitrogen aeration in 30 ml of N,N-diethylaniline. After cooling, the mixture is stirred into 300 ml of 4 N hydrochloric acid, the resulting emulsion is extracted three times with 50 ml of ethyl acetate, and the organic extracts are combined, dried over calcined potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After evaporating the appropriate fractions, the title compound is obtained as an oil.
Reaction SMILES: [N+:1]([CH2:4][C:5](=O)[CH3:6])([O-:3])=[O:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:5]([CH3:6])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:11][N:10]=1
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Nitroacetone (1.1 g) and N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g) were dissolved in toluene (60 ml), and the solution was refluxed for 3 hours in a flask equipped with a water separating device while removing water formed by the reaction. Toluene was concentrated under reduced pressure, and the remaining solid was recrystallized from ethanol to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methyl-2-nitrovinyl)ethylenediamine (2.0 g) having a melting point of 78° to 80° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]([NH2:4])=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>N1C=CC=CC=1>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]#[N:4]
Reactant: CCOC(=O)CCCCCCNC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCCCCCNC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 7-ureidoheptanoate (2.1 g., 0.01 mole) in pyridine (10 ml.) is added p-toluenesulfonylchloride (2.0 g., excess). The reaction is stirred at room temperature for two hours, poured into water (100 ml.), then extracted with ether (2 × 100 ml.). The ether is washed with 5% hydrochloric acid (2 × 25 ml.), brine, then dried over sodium sulfate. The solvent is removed in vacuo to give ethyl 7-cyanamidoheptanoate as a light yellow oil, yield 1.7 g. (86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:17])=[N:4][C:5](F)=[C:6]([C:14]=1F)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+]>C1COCC1>[C:19]([O:21][C:5]1[N:4]=[C:3]([I:17])[C:2]([Cl:1])=[C:14]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([CH3:22])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)c1c(F)nc(I)c(Cl)c1F
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(OC(C)(C)C)nc(I)c(Cl)c1OC(C)(C)C
Yield: 86.4 %

Procedure:
Into a solution of tert-butyl 5-chloro-2,4-difluoro-6-iodonicotinate (0.4 g, 1.1 mmol) in THF (2.3 mL) at −78° C. was added a solution of potassium tert-butoxide (1.0 M×2.3 mL, 2.3 mmol). The temperature was allowed to rise to room temperature and the reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, evaporated and purified by silica chromatography (0-20% ethyl acetate in hexanes) to give tert-butyl 2,4-di-tert-butoxy-5-chloro-6-iodonicotinate (0.23 g, 44%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.ClC1C2C(=CC(OC)=C(OC3CCC4(OCCO4)CC3)C=2)N=CN=1.[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH2:57]>C(#N)C.C(N(CC)CC)C>[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH:57][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Agent: COc1cc2ncnc(Cl)c2cc1OC1CCC2(CC1)OCCO2
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cc(C)ccc3F)c2cc1OC1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6 ml phosphorus oxychloride are added dropwise to 12.1 g 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and after standing overnight half the solution of the intermediate product (4-chloro-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline, see Example IX) is combined dropwise with 2.7 ml of 2-fluoro-5-methylaniline in 5 ml acetonitrile. The reaction mixture is heated to 40° C. for 3 hours, then cooled and evaporated down. The residue is mixed with water and stirred. The precipitate formed is suction filtered and divided between 1M sodium hydroxide solution and dichloromethane. The organic phase is separated off, dried, evaporated down and stirred with diisopropylether. The solid is suction filtered and dried.
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].C([OH:19])(C)(C)C.O>C(OCC)(=O)C>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:19])=[O:11])=[CH:8][C:7]=1[F:14]
Reactant: CC(C)(C)O
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c(F)c1
Reaction time: 96 h

Procedure:
Sodium chlorite (17 g) was added dropwise to a mixture of 4-chloro-3-fluorobenzaldehyde (10 g), amidesulfuric acid (18 g), tert-butyl alcohol (50 mL), and water (50 mL) under ice cooling. The temperature of the mixture was returned gradually to room temperature, and the mixture was stirred for 4 days. The reaction mixture was diluted with ethyl acetate, and the resultant mixture was washed with water, 1N hydrochloric acid, and saturated brine. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was recrystallized from a solvent mixture of diisopropyl ether and hexane, to thereby give the title compound (11.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1nc(I)oc1-c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(I)oc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a stirred solution of methyl 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylate (20.0 g, 55.2 mmol) in EtOH (300 mL) was added a solution of NaOH (3.3 g, 82.8 mmol) in water (100 mL). The reaction mixture was allowed to stir at rt overnight and was then acidified by the addition of 1M HCl. The solution was concentrated to a small volume and then extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylic acid (12.0 g, 60%).