Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[CH:28](O)=O.C=O>[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:28])[CH2:18]3)[S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCNC1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Temperature: 60 °C

Procedure:
A mixture of N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-pyrrolidin-3-yl-methanesulfonamide (200 mg), formic acid (2.5 mL) and formaldehyde (37% solution, 0.37 mL) was heated at 60° C. overnight. The mixture was diluted with 2M NaOH then extracted with CH2Cl2. Combined extracts were dried (MgSO4), filtered and concentrated. Purification on silica yielded N-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamide (38 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[N+]([O-])(O)=O.CC1C=C(C)[N:18]([C:22](N)=[NH:23])N=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH:6][C:22]([NH2:23])=[NH:18]
Reactant: NCc1ccc(N)c(I)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)NCc1ccc(N)c(I)c1

Procedure:
An ethanol (5 ml) solution of 3-iodo-4-aminobenzylamine (0.220 g, 0.887 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.179 g, 0.087 mmol) was heated at reflux temperature for 3 hr. under argon. The solvent was evaporated in vacuo and the residue washed with ether and dichloromethane to remove 3,5-dimethylpyrazole and unreacted amine. The crude product was recrystallized from methanol/ether to give fine, pale-yellow needles (0.163 g, 72.5%), mp 135°-137° C.; PMR (DMSO-d6) γ6.62-7.66 (m, 9H), 4.1 (s, 2H); IR (Nujol) 1660, 1620 cm-1 (C=N); Anal. Calcd. for C18H11IN4. HNO3.0.5H2O): C, 27.20; H, 3.42, N, 19.08. Found C, 26.70; H, 3.33; N, 19.08.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7](O)=[CH:8][CH:9]=1)=[O:3].[OH2:11].Cl.N([O-])=[O:14].[Na+]>>[OH:11][C:1](=[O:14])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(=O)c1ccccc1
Temperature: 10 °C

Procedure:
Reactor. A 12-liter, 4-neck, jacketed flask with bottom drain valve is charged with 4-hydroxyacetophenone (4-HAP, 619 g, 4.6 moles), H2O (2622 g, 145.7 moles) and HCl (887 g of a 32% aqueous solution, 7.8 moles). The flask is equipped with a mechanical stirrer (glass shaft, TFE stir paddle), gas inlet tube adaptor with subsurface sparge tube, nitrogen inlet, thermowell, and gas outlet adaptor. The reactor is connected to the generator using 1/4" OD TFE tubing which is piped such that the stream of NOCl can be diverted to a scrubber which consists of a 500 ml vacuum flask with rubber stopper drilled to accommodate the 1/4" tubing. Similarly, the outlet from the reactor is connected to a separate scrubber. The scrubbers are charged with 250 ml of a 20% NaOH aqueous solution. The reaction flask contents are stirred and flask is purged with nitrogen to remove residual air. The temperature of the reaction flask is set to 45° C. using a chiller/circulator. Once the NaNO2 is added to the generator, the nitrogen purge is stopped and the gas bubbles in the scrubber can be observed to coincide with the rate of the NaNO2 addition. By lowering the set-point of the chiller, the temperature of the exothermic reaction is maintained below 50° C. The 4-HAP is observed to go into solution when about 2/3 of the NaNO2 has been added to the generator. After the addition is complete, the NOC1 stream is diverted to the scrubber and the nitrogen sparge is resumed in the reactor (subsurface) to remove excess NOC1 for thirty (30) minutes. The chiller is then set to cool the stirred reactor contents to 10° C. During this cool-down, the tancolored hydroxyphenyl glyoxal (HPGO) crystals fall out of solution. The slurry is drained and filtered through a fritted coarse Buchner to afford a tan solid (961 g, 54.6% pure, 69% isolated/84.2% total yield HPGO).
Reaction SMILES: C([NH:4][CH:5](C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[CH:21]([CH2:22][N:23]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[O:27])[N:24]=3)[CH2:20]C[C:18]=2[CH:39]=1.C1(C)C=CC(S(C#N)(=O)=[O:47])=CC=1.[NH4+].[Cl-]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[C:21]([C:5]#[N:4])([CH2:20][O:47][C:18]=2[CH:39]=1)[CH2:22][N:23]([C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=1)=[O:27])[N:24]=3
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC2CCc3cc(Cl)ccc3C2=N1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC12COc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a solution of diisopropylamine (0.42 mL, 3.0 mmoles) in 10 mL of THF was added, n-butyllithium (1.9 mL of 1.6M, 3.0 mmole) at -78° C. under N2. After 15 min, a solution of the product of Step D (0.5 g, 1.3 mmole) in 3 mL of THF was added dropwise and the dark red solution that formed was stirred at -78° C. for an additional 15 min. Then, p-toluene-sulfonyl cyanide (0.31 g, 1.7 mmole) in 2 mL of THF was added dropwise to the reaction mixture which decolorized near the end of the addition. Saturated aqueous NH4Cl was added and the reaction was allowed to warm to room temperature. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (MgSO4) and concentrated (vacuum). The resulting solid was triturated with ether to afford the title compound (0.36 g, 66% yield) as a white solid, mp 227°- 229° C. 1H NMR (CDCl3): δ8.10 (s, 1H), 7.91 (d, 1H), 7.62 (ABq, 4H), 7.30 (m, 2H), 4.79 (d, 1H), 3.81 (d, 1H), 3.41 (m, 1H), 3.04 (m, 1H), 2.68 (m, 1H), 2.15 (td, 1H).
Reaction SMILES: [C:1]([O:5]C)(=O)[C:2]#[CH:3].[NH2:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1>>[NH:7]1[C:8]2[CH2:9][CH2:3][CH2:2][C:1](=[O:5])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:14]
Reactant: C#CC(=O)OC
Reactant: NC1=CC(=O)CCC1
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 105 °C
Yield: 28 %

Procedure:
Methyl propiolate (5.03 ml, 56.2 mmol) was added to finely ground 3-aminocyclohex-2-enone (5 g, 45.0 mmol). The resulting mixture was heated to 105° C. resulting in a dark brown solution and stirred under reflux for 60 min. Then the reflux condenser was removed and the excess methyl propiolate was distilled off by raising the temperature to 170° C. The reaction mixture was cooled to RT and the resulting solid was triturated with dichloromethane (10 mL) and heated to 40° C. for 25 min. The hot mixture was filtered and the yellow residue was washed with dichloromethane (10 mL). The solid was dried under reduced pressure. Amount 2.07 g. Yield 28%.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(-c2cccc(Cl)c2)n2c1c(C)nc1ccc(F)cc12
Yield: 95.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-chlorophenylboronic acid (48 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (78 mg, 96% yield). EIMS 326.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[N:12][OH:13])=[O:4].Cl[C:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16].C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:46]=[C:45]2[C:40]([C:41]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:42][C:43]([NH2:47])=[N:44]2)=[CH:39][CH:38]=1>>[NH2:47][C:43]1[CH:42]=[C:41]([N:48]2[CH2:53][CH2:52][N:51]([C:15]([O:13][N:12]=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:16])[CH2:50][CH2:49]2)[C:40]2[C:45](=[CH:46][C:37]([Cl:36])=[CH:38][CH:39]=2)[N:44]=1
Reactant: COC(=O)C1CCCCCC1=NO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCCCC1=NOC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for 78, 2-methoxycarbonyl-cycloheptanone-oxime, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 474 (M++1). 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.60 (s, 1H), 7.18 (d, 1H), 6.15 (s, 1H), 4.80 (s, 2H), 3.80 (m, 5H), 3.75 (s, 3H), 3.15 (m, 4H), 2.90 (m, 1H), 2.40 (m, 1H), 2.05 (m, 2H), 1.72 (m, 2H), 1.60 (m, 3H), 1.45 (m, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[C:21]12([CH2:31][N:32]=[C:33]=[O:34])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.Cl>O1CCCC1.CCCCCC>[C:21]12([CH2:31][NH:32][C:33](=[O:34])[C:18]3[C:17]([Cl:20])=[CH:16][N:15]=[C:14]([Br:13])[CH:19]=3)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: Clc1ccc(Br)nc1
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a stirred solution of di-isopropylamine (2.1 ml) in anhydrous tetrahydrofuran (15 ml) at is −5° C. was added, dropwise a solution of n-butyl lithium in hexane (2.5 molar, 4.8 ml) and the resulting solution was stirred for 30 minutes and was then cooled to −70° C. To the cooled solution was added a solution of 2-bromo-5-chloropyridine (2.39 g) in anhydrous tetrahydrofuran (10 ml) maintaining the internal temperature of the reaction below −65° C. The reaction was maintained at −70° C. for 15 minutes and then a solution of 1-adamantylmethyl isocyanate (1.91 g) in anhydrous tetrahydrofuran (5 ml) was dropwise added (care exotherm). The mixture was stirred for 10 minutes and was then poured into a solution of 1M aqueous hydrochloric acid solution (50 ml) and the mixture extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:iso-hexane (1:9 to 1:4 to 1:1) to afford the sub-titled compound (2.70 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:11][C:12]1([C:18]([O:20][CH2:21]C)=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.CN1CCCC1=O>O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:15]2[CH2:16][CH2:17][C:12]([CH3:11])([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)CCN(c2ncc(Br)cc2F)CC1
Temperature: 210 °C
Yield: 47.7 %

Procedure:
5-Bromo-2-chloro-3-fluoropyridine (100 mg, 0.475 mmol), ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol), ethyldiisopropylamine (248 uL, 1.426 mmol) and 1-methyl-pyrrolidin-2-one (0.5 mL) were transferred to a microwave reaction vial. The vial was sealed and heated at 210° C. for 15 minutes. A further portion of ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol) was added and the reaction mixture heated for a further 15 min at 210° C. The reaction mixture was diluted with water (25 mL), the pH adjusted to 3 using 1 M HCl, before extraction with DCM (3×25 mL). The organic fractions were combined, dried (cotton wool plug) and concentrated in vacuo to give a crude brown oil. Flash chromatography on silica gel, eluting with DCM (0-100% gradient) in n-hexane gave an impure mixture which was further purified using flash chromatography on silica gel, eluting with 0-4% EtOAc gradient, 4% isocratic, then 4-10% EtOAc in n-hexane to obtain the desired product (75 mg, clear oil). 1H NMR (Acetone) δ 8.05 (dd, J=2.0, 1.1 Hz, 1H), 7.60 (dd, J=12.6, 2.0 Hz, 1H), 4.17 (q, J=7.1 Hz, 1H), 3.83-3.75 (m, 1H), 3.16-3.07 (m, 1H), 2.19-2.11 (m, 1H), 1.60-1.50 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.22 (s, 3H). m/z 345.0, 346.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([C:48](=[O:52])[C:49](Cl)=[O:50])=[CH:40]1.CO>C(Cl)Cl>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([C:48](=[O:52])[C:49]([N:16]2[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]3[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[C:18]=3[CH2:17]2)=[O:50])=[CH:40]1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)C(=O)c1c[nH]c3ccccc13)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 2-(1H-indol-3-yl)-2-oxoacetyl chloride (14.5 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product was repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate collected by filtration to give 2-(6-(2-(1H-indol-3-yl)-2-oxoacetyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (2.4 mg, 16% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (0.5H, d, J=5.80 Hz), 8.13 (0.5H, d, J=7.32 Hz), 8.05 (0.5H, s), 7.82 (0.5H, s), 7.48-7.68 (2H, m), 7.24-7.48 (4H, m), 7.09 (0.5H, t, J=5.80 Hz), 6.80-6.92 (0.5H, m), 6.71-6.80 (0.5H, m), 6.59-6.71 (0.5H, m), 4.72 (0.5H, s), 4.58 (0.5H, d, J=18.01 Hz), 4.37 (1H, dd, J=17.24, 8.09 Hz), 3.96 (0.5H, d, J=16.79 Hz), 3.77-3.93 (1H, m), 3.55-3.72 (2.5H, m), 1.49 (3H, d, J=7.02 Hz), 1.23-1.38 (6H, m), 1.17 (3H, t, J=5.80 Hz), 0.85-1.05 (9H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.51. LCMS (M+H) calcd for C35H39FN3O5: 600.28. found: 600.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:28])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 2-ethoxy-1-(4-chloro-2-fluoro-5 -methoxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone. m.p. 117°-119° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCO)c1
Yield: 96.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 3-bromo-1-propanol (500 mg, 3.6 mmol) were added. The mixture was heated to reflux for 2 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried on Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 520 mg (yield 95%) of title product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([CH2:12][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:7]=2)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Oc1cncc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1COc1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 3-fluoro-5-hydroxypyridine (34 mg, 0.30 mmol) in dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 12 mg, 0.30 mmol) at 0° C. and the mixture was stirred at room temperature for 15 minutes. To the mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (100 mg, 0.4 mmol) in dimethylformamide and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel to afford 47 mg (53%) of the title compound:
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]([Br:30])=[CH:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][C:23]2([CH2:27][CH2:28][CH3:29])[CH2:26][O:25][CH2:24]2)=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Br:30][C:11]([Br:10])=[CH:12][CH:13]1[CH2:14][CH2:15][CH:16]([C:19]23[O:21][CH2:22][C:23]([CH2:27][CH2:28][CH3:29])([CH2:26][O:25]2)[CH2:24][O:20]3)[CH2:17][CH2:18]1
Reactant: CCCC1(COC(=O)C2CCC(C=C(Br)Br)CC2)COC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC12COC(C3CCC(C=C(Br)Br)CC3)(OC1)OC2
Temperature: 25 °C

Procedure:
Boron trifluoride etherate (40 μl) was added to a stirred solution of 3-propyloxetan-3-ylmethyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (0.57 g) in dry dichloromethane (10 ml) at -70° C. The mixture was allowed to warm to room temperature over 16 hours. Triethylamine (0.6 ml) was then added. The organic phase was washed with brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on alumina eluting with 3:7 dichloromethane:hexane saturated with ammonia. 1-[4-(2,2-Dibromovinyl)cyclohexyl]-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless oil (0.34 g).
Reaction SMILES: N1[CH:5]=[CH:4]N=C1.FC(F)(F)OC1C=CC([C:15](C2C=CC(OC(F)(F)F)=CC=2)([OH:23])[CH:16]([N:18]2[N:22]=[N:21][CH:20]=[N:19]2)[CH3:17])=CC=1.S(Cl)(Cl)=[O:38].O>C(#N)C>[CH2:4]([O:38][C:15](=[O:23])[CH:16]([N:18]1[N:22]=[N:21][CH:20]=[N:19]1)[CH3:17])[CH3:5]
Reactant: c1c[nH]cn1
Reactant: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)n1ncnn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of imidazole (1.23 g) and 1,1-bis(4-trifluoromethoxyphenyl)-1-hydroxy-2-(2H-tetrazol-2-yl)propane prepared as described in Example b 3 (1.34 g) in dry acetonitrile (50 ml) under an atmosphere of nitrogen, was added thionylchloride (1.07 g). A precipitate appeared and the reaction was stirred at room temperature for 5 hours. The mixture was then poured into water (100 ml) and extracted with ether (2×70 ml). The organic extracts were combined and washed well with saturated aqueous sodium bicarbonate solution (50 ml) then with water (50 ml). The organic layer was dried over anhydrous magnesium sulphate, and evaporated to give a yellow oil which was purified by h.p.l.c. on a silica gel column eluted with n-hexane/ethyl acetate (5:1) to give a colourless oil (900 mg).
Reaction SMILES: C(O)C.CC1[N:6]([C:11]2[CH:23]=[CH:22][C:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=2)C(C)=CC=1.Cl.NO>C(N(CC)CC)C>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[CH:22]=[CH:23][C:11]([NH2:6])=[CH:12][C:13]=2[C:24]([F:25])([F:26])[F:27])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C)n1-c1ccc(Cc2ccncc2)c(C(F)(F)F)c1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(Cc2ccncc2)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To 10 mL of an ethanol solution of 227 mg (0.69 mmol) of 4-[4-(2,5-dimethyl-pyrrol-1-yl)-2-trifluoromethyl-benzyl]-pyridine, 191 mg (2.75 mmol) of hydroxylamine hydrochloride and 200 μL of triethylamine were added and the mixture solution was refluxed with stirring for 18 hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=1:1) to obtain 144 mg (83%) of a target product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[CH2:36]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:36][C:35]([F:46])([F:45])[F:34])[CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(CC(F)(F)F)CC3)c2)nc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (350 mg) and diisopropylethylamine (685 μL) in N,N-dimethylformamide (3.5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (433 μL), followed by reacting at room temperature for 2 hours. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1-90:10) to obtain 5-chloro-6-ethyl-3-({1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide (424 mg) as a yellow solid.