Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[H-].[Na+].Br[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][C:19]([CH3:22])([CH3:21])[CH2:20][N:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:13][CH3:14])=[C:2]([F:1])[C:7]=2[N:8]([CH3:12])[C:9]1=[O:11]
Reactant: CC(C)(C)CBr
Reactant: COc1ccc2[nH]c(=O)n(C)c2c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1F)n(C)c(=O)n2CC(C)(C)C
Reaction time: 0.42 h

Procedure:
A solution of 7-fluoro-6-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-4, 250 mg, 1.27 mmol) in anhydrous DMF (1.5 ml) was treated with NaH and 1-Bromo-2,2-dimethylpropane. The reaction was then irradiated in a microwave at 175 deg C. for 25 min. The reaction was partitioned between EtOAc (2×60 ml) and water (75 ml). The combined organic layers were dried over Na2SO4 and concentrated, affording the title compound, 1-(2,2-dimethylpropyl)-4-fluoro-5-methoxy-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-5), as an orange oil. 1H NMR (300 MHz, CDCl3) δ 6.65-6.70 (m, 2H), 3.88 (s, 3H), 3.60 (m, 5H), 1.03 (s, 9H). LRMS m/z: Calc'd for C14H19FN2O2(M+H) 267.3, found 267.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][C:43]([CH:46]3[CH2:48][CH2:47]3)=[CH:44][CH:45]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][C:43]([CH:46]3[CH2:47][CH2:48]3)=[CH:44][CH:45]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J29) (260 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (283 mg, 62%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:25]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:26]=[C:27]([CH3:29])[CH:28]=1)=[O:4].[OH-].[Li+]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C@H:8]2[CH2:7][N:6]([C:24]3[N:25]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[N:26]=[C:27]([CH3:29])[CH:28]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:12])=[O:11])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound brown solid which was used in the next step without further purification. MS (ESI): m/z=538.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.B(F)(F)F>C1C=CC=CC=1.CCOCC>[CH3:9][C:4]1([CH3:8])[CH:3]2[C:2](=[CH2:1])[CH:7]([CH:12]([CH3:13])[CH2:11][C:10]2=[O:14])[CH2:6][CH2:5]1
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1C2CCC(C)(C)C1C(=O)CC2C

Procedure:
A solution of 2,6,6-trimethyl-1-crotonoyl-2-cyclohexene (1.0 g.) in a mixture of benzene and ether (10 ml.) was heated at ca. 80° in the presence of a catalytic amount of a saturated solution of BF3 in ether. The course of the reaction was followed by v.p.c. analysis. Three hours were usually necessary for converting the starting material into the bicyclic compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](N)=[O:14]>>[CH:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14]
Reactant: NC=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=CN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The process of claim 6 in which a slurry of L-phenylalanine in formamide is heated to form N-formyl-L-phenylalanine.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][OH:13].O=CCCCNC(=O)C1C=CC=CC=1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]=[O:13]
Reactant: OCCN1CCc2ccccc2C1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCN1CCc2ccccc2C1

Procedure:
(3,4-Dihydro-1H-isoquinolin-2-yl)-acetaldehyde (31B) is prepared from 31A as described for 1E.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH:16]2C)[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:32]O>[Pd]>[CH:23]1([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C@@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH2:20][CH2:19]2)[CH2:22][CH2:32]1
Reactant: CC1CN(C2CC2)CCN1[C@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CO
Agent: [Pd]
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
8.5 g (20 mmol) cis-dibenzyl-[4-(4-cyclopropyl methyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 170 ml of methanol and hydrogenated on 1.7 g Pd/C (10%) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and conc. HCl. Yield: 4.4 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[O:30]>>[Si:7]([O:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:2]([C:23]2([OH:30])[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[NH:25][C:24]2=[O:29])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Br
Product: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 60.5 %

Procedure:
With 100 g of the compound obtained in Step 204-2 and 45.8 g of 5-chloroisatin as starting material, 66.2 g of the title compound (opal solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[C:21]([NH:28][C:29]([C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)=[O:30])[CH:20]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([NH:28][C:29]([C:31]3[N:32]=[C:33]([CH3:36])[S:34][CH:35]=3)=[O:30])[CH:20]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cccc(C#N)c3)cc3[nH]ncc23)cs1
Temperature: 150 °C

Procedure:
(3-Cyanophenyl)boronic acid (17 mg, 0.12 mmol), 0.6 M potassium carbonate (aq) (0.2 ml, 0.12 mmol) and Pd(dppf)Cl2 (10 mg, 0.014 mmol) in 1,4-dioxane (1 ml) were treated with N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (40 mg, 0.12 mmol) in 1,4-dioxane (1 ml). The reaction was heated in a CEM Discover microwave at 150° C. for 30 mins. After cooling the solvent was removed in vacuo. The residue was dissolved in MeOH and loaded onto a C18 SPE cartridge eluting with 0.1% TFA in MeCN (3×3 ml). The solvent was removed under a stream of nitrogen. The residue was purified by MDAP (Method C) to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]([C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[S:7]([C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:12]([CH3:23])[CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[S:7]([C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:12]([CH3:23])[CH:11]=2)(=[O:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Yield: 43.1 %

Procedure:
To a solution of ethyl [4-({(2-cyclopropylethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)-2-methylphenoxy]acetate (156 mg, 0.28 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH aq. (1 mL, 2 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (2×20 mL) and 2M HCl (20 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo. Purification by SPE (5 g aminopropyl cartridge), loading crude material in CH2Cl2 and then washing with MeOH, prior to eluting with 5% NH3 in MeOH. The 5% NH3 in MeOH extract was concentrated in vacuo and the residue was partitioned between CH2Cl2 (20 mL) and 2M HCl (2 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo affording the title compound as a white solid (64.4 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[C:7]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[C:7]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.20 g, 2.83 mmol), NBS (0.656 g, 3.68 mmol), and diphenylperoxyanhydride (0.069 g, 0.283 mmol) in carbon tetrachloride (20 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used directly in the next step without further purification. MS (m/z) 504.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:27]2([CH3:28])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19](OC)=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:30][CH2:31][O:32][CH3:33])[CH2:6]1.COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(OC)=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:27]2([CH3:28])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH3:18])[CH2:19][OH:20])[CH2:8][C@@H:7]([O:30][CH2:31][O:32][CH3:33])[CH2:6]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 77 %

Procedure:
The procedure of Example 11 was repeated except that 65 mg of methyl 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carboxylate was used in lieu of 70 mg of methyl 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20 carboxylate to give 47 mg of 1α,3β-bis(methoxymethoxy)-20methylpregna-5,7-diene-21-ol, whose 1H NMR spectrum was identical with that obtained in Example 10.
Reaction SMILES: [O-][O-].[Na+].[Na+].[C:5]1([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1.S(Cl)(Cl)=O.C1(CCC2C=CC=CC=2)C(C(Cl)=[O:33])=CC=CC=1.[OH-].[Na+].OO.OO.[OH-].[Na+].[CH2:51]([C:59]1[CH:67]=[CH:66][C:62]([C:63]([Cl:65])=[O:64])=[CH:61][CH:60]=1)[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1.O>[CH2:14]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][O:64][C:63](=[O:33])[C:62]2[CH:66]=[CH:67][C:59]([CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:60][CH:61]=2)=[O:12])=[CH:9][CH:10]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[C:59]1([CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:60]=[CH:61][C:62]([C:63]([Cl:65])=[O:64])=[CH:66][CH:67]=1
Reactant: O=C(Cl)c1ccccc1CCc1ccccc1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Agent: O=C(Cl)c1ccc(CCc2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(OOC(=O)c1ccc(CCc2ccccc2)cc1)c1ccc(CCc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
This peroxide was synthesized from the corresponding acid chloride and sodium peroxide. First, 4-bibenzylcarboxylic acid chloride was prepared from 4-bibenzylcarboxylic acid and thionyl chloride (see the synthesis of 2-bibenzylcarboxylic acid chloride above). The acid chloride was purified by vacuum distillation (bp=104-106° C./120-130, μHg), and solidified upon cooling. The synthesis of the peroxide was performed with NaOH/H2O2 and the acid chloride in tetrahydrofuran. Here, 12.0 ml 30% H2O2 was added to 4.8 g NaOH in 30.0 ml H2O and the solution cooled to 5° C. A solution of 2.0 g 4-(phenethyl)benzoyl chloride in 2.0 ml tetrahydrofuran was then added and the reaction mixture stirred for one hour. The crude peroxide was filtered off and recrystallized from chloroform/methanol, mp=145° C. (decomp.). The yield was 41%. The peroxide proved to be quite insoluble in common solvents, except for chloroform and large amounts of benzene. NMR δ(ppm): 2.9-3.0 (m, 8, —CH2—CH2—), 7.1-7.3, 7.9-8.0 (m, m, 18, aromatic H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (20 g, 79 mmol) and phosphoryl chloride (36.0 mL, 395 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (17.35 g, 81%). NMR (DMSO-d6) δ 7.71 (s, 1H), 7.73 (s, 1H), 7.88 (d, 2 H, J, J=8.1 Hz), 8.05 (d, 2 H, J, J=8.1 Hz) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)ncn1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.22 g of benzyl alcohol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.5 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by stirring at 0° C. for 1.5 hours and then further stirring at room temperature for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.43 g of 4-chloro-6-benzyloxypyrimidine.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.P(Cl)(Cl)([Cl:28])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:28][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
2300 mg (6.5 mmol) of ethyl 5-hydroxy-7-[4-(trifluoromethyl)phenyl][1,2,4]triazolo-[1,5-c]pyrimidine-2-carboxylate (Example 133A) are introduced into phosphoryl chloride (30 ml), 5.95 g (26.1 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 20 h. The reaction mixture is slowly poured, while stirring vigorously, into saturated sodium bicarbonate solution (200 ml) and ice, and solid sodium bicarbonate (approx. 20 g) is added until a pH of 8 is reached. The solid is filtered off with suction and washed with water and diethyl ether and dried. 2300 mg (92% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([F:21])[CH:12]=2)=[N:4][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CC3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(C2CC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To methyl 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoate (250 mg, 0.870 mmol) in THF (6 mL) and MeOH (3 mL) was added 1M LiOH (1.740 mL, 1.740 mmol). The reaction mixture was stirred at room temperature for 2 h. The pH of reaction mixtures was adjusted to ˜4 by aqueous. 2N HCl. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated to yield 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoic acid (230 mg, 97%) as a light yellow solid. LCMS (m/z): 274.2 (MH+), 0.621 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(Cl)c(Cl)c2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)c(Cl)c1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3,4-dichlorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dichlorobenzyl ester of melting point 149° C (from ethanol).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CI.CN(P(N(C)C)(N(C)C)=O)C.[Cl-].[NH4+]>C1COCC1>[CH3:1][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCC(C)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of diisopropylamine (9.0 ml, 64.4 mmol) in 100 ml anhydrous THF was added dropwise n-butyl lithium (1.61N, 40.0 ml, 64.4 mmol) at -78° C. under argon atmosphere. The mixture was stirred at -78° C. for 30 minutes and ethyl nonanoate (10.00 g, 53.7 mmol) was added dropwise. After stirring the mixture at -78° C. for 30 minutes, a solution of methyl iodide (3.7 ml, 59.1 mmol) in HMPA (2.8 ml, 16.1 mmol) was added dropwise and the mixture was stirred at -78° C. for 3.5 hours. Saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction mixture and the resulting mixture was then extracted with ether (50 ml×4). The ether layers were washed with water (50 ml) and with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Distillation gave yellow liquid, ethyl 2-methylnonanoate (9.6892 g, yield: 90.1%, b.p.: 63°-64° C./0.7 mmHg). The structure of this product was confirmed by the following data.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:7])C.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl.CCCCCC>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([CH3:7])=[CH:5][CH2:4][OH:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C=C(C)c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=CCO)c1ccc(Cl)cc1
Yield: 37.6 %

Procedure:
The above ester (1.44 g) was dissolved in dichloromethane (13 ml) and cooled to -20°. Diisobutylaluminium hydride (12.8 ml of a 1M solution in hexane) was added dropwise. After 18 hours at 25° dilute hydrochloric acid was added carefully and the mixture worked up in the usual manner to give 3-(4-chlorophenyl)but-2-en-1-ol (0.44 g). NMR 1H: 7.18(4H,s), 5.85(1H,t), 4.25(2H,d), 3.05(1H,s), 2.05(3H,s).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH3:26])[CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[F:27][CH:28]([F:43])[O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]OS(C)(=O)=O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:37][CH2:36][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:43])=[CH:35][CH:34]=4)[CH2:22]3)[CH2:18]2)[CH3:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Reactant: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCN1CC2CN(CCc3ccc(OC(F)F)cc3)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyano-N-methyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.169 g, 0.40 mmol, prep. I above), methanesulfonic acid 2-(4-difluoromethoxy-phenyl)-ethyl ester (0.107 g, 0.40 mmol, prep W above ), potassium carbonate (0.177 g, 1.28 mmol), and water (0.1 mL) in acetonitrile (4 mL) was heated in an oil bath (60° C.) for 20 h. Solid material was filtered off and the filtrate was loaded onto a cation-exchange column (SCX-2, Isolute™, 2 g/15 mL). The column was washed with a solution of methylene chloride/acetonitrile/methanol (2:1:1, 40 mL) and eluted with 20% methanol saturated with ammonia in methylene chloride (30 mL). The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane eluent. Concentration in vacuo afforded 118 mg (57%) of the title compound as a solid white material.