Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[Na+].[OH-].[Na+].C([O-])=O.C1N=C(N)C2N=CN([C@@H]3[O:23][C@H:22]([CH2:24][O:25][P:26]([O:29]P(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)([OH:28])=[O:27])[C@@H:21]([OH:51])[C@H]3O)C=2N=1>>[CH2:21]([OH:51])[C:22]([CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])=[O:23]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(CO)COP(=O)(O)O

Procedure:
For removing dX1P the acetaldehyde was evaporated and the solution was diluted with water to reach 30 ml. It was mixed with 3 ml 2.65 M sodium formate solution (8 mmol), and sodium hydroxide solution was added until a pH of 7.4 was reached. 23 U formate dehydrogenase (FDH), 6 mg NADH, 16 U RAMA and 20 U glycerolphosphate dehydrogenase (GDH) were added.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[CH2:24]([N:31]1[CH2:35][CH2:34][N:33]([C:36]2[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH2:35][CH2:34][N:33]([C:36]2[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 84% yield: mp 248-249° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.22 (m, 5H), 4.47 (s, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 318.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)C(O)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
A 250 mL round bottom flask containing 5.6 g (30 mmol) of p-chlorophenyl-α-hydroxyacetic acid and 100 mL of concentrated HCl:MeOH (1:9) was warmed to reflux for 12 hours. The solution was concentrated under reduced pressure, diluted with 250 mL of Et2O and washed once with 30 mL of H2O, twice with 30 mL of NaHCO3 solution, once with 30 mL of H2O and once with 30 mL of brine. The organic layer was dried (Na2SO4) and concentrated leaving 5.0 g (83%) of methyl p-chlorophenyl-α-hydroxyacetate lit m.p. 55° C.) 1H-NMR (CDCl3) δ7.36-7.28 (m, 4H), 5.13 (s, 1 H), 3.72 (s, 3H), 3.67 (br s, 1 H (exchanges with D2O)).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9]CC)=O.[F:18][C:19]([F:24])([F:23])[C:20](N)=[NH:21]>C(O)C>[C:12]1([C:5]2[C:6]3[C:7](=[O:9])[NH:21][C:20]([C:19]([F:24])([F:23])[F:18])=[N:1][C:2]=3[S:3][CH:4]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N=C(N)C(F)(F)F
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (2 g, 8.087 mmol) and trifluoroacetamidine (4.531 g, 40.44 mmol) were combined in ethanol (20 mL) and heated to reflux overnight. Further trifluoroacetamidine (4.531 g, 40.44 mmol) was added and the reaction heated to reflux for a further 18 hours. The reaction mixture was allowed to cool to room temperature. The resulting precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuo at 40° C. to afford 5-phenyl-2-(trifluoromethyl)-3H-thieno[2,3-d]pyrimidin-4-one (1.195 g). LCMS: purity 99%, RT=4.11 min, M+1=297.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1
Reactant: Brc1ccc(C2OCCO2)s1
Reactant: Fc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(Cc2ccc(C3OCCO3)s2)c1
Reaction time: 0.28 h
Yield: 13.9 %

Procedure:
n-Butyl lithium (2.44N hexane solution, 6.4 mL, 16.9 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (3.0 g, 13 mmol) in tetrahydrofuran (30 mL) at from −75° C. to −69° C., and the solution was stirred for 17 minutes. 3-Fluorobenzyl bromide (1.7 mL, 14.3 mmol) was added dropwise to this reaction solution at from −75° C. to −69° C. After dropwise addition was completed, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (478 mg, 1.81 mmol, 13.9%) was obtained as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=C[C:30](C#N)=[C:29](N)[CH:28]=2)[CH:21]([C:36]([O:38][CH3:39])=[O:37])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]1[CH:45]=[N:44][CH:43]=[N:42][CH:41]=1.CC(O)=O>CCO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[C:41]3[C:30]([C:45]([NH2:40])=[N:44][CH:43]=[N:42]3)=[CH:29][CH:28]=2)[CH:21]([C:36]([O:38][CH3:39])=[O:37])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ncncn1
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 24.9 %

Procedure:
A solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol), 1,3,5-triazine (146 mg, 1.81 mmol), and glacial HOAc (99 mg, 1.81 mmol) in absolute EtOH (10 mL) is maintained at reflux for 16 hours. A second portion of 1,3,5-triazine (146 mg, 1.81 mmol) and glacial HOAc (99 mg, 1.81 mmol) is added and the reaction mixture is maintained at reflux for an additional 16 hours. The reaction mixture is concentrated in vacuo and the crude product is diluted with water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 26 mg (20%) of the title compound as a white solid which is used directly in the next reaction without further characterization.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([OH:23])([CH2:16]3)[CH2:14]1)[CH2:20]2>C1COCC1.CN(C=O)C>[C:1]([NH:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([OH:23])([CH2:16]3)[CH2:14]1)[CH2:20]2)(=[O:3])[CH3:2]
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC12CC3CC(CC(O)(C3)C1)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 11 mmole of acetyl chloride and 12 mmole of triethylamine were dissolved in 2 mL of THF. To the resultant mixture, 10 mmole of a solution of 1-amino-3-adamantanol in DMF (10 mL) was added dropwise over 30 minutes at 40° C. The mixture was stirred for another 3 hours at 40° C. As a result, the conversion of 1-amino-3-adamantanol was 99%, and 1-acetylamino-3-adamantanol (yield 95%) was formed.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[I-:26].[Na+]>[Cu]I>[F:8][C:6]1[CH:7]=[C:2]([I:26])[CH:3]=[C:4]([F:25])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: [I-]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(I)cc3F)CC2)c(C)c1
Yield: 81.3 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (820 mg) described in Preparation Example 111, sodium iodide (599 mg) and copper(I) iodide (189 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (743 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.Cl[C:14]1[N:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: O=Cc1cc(Br)cc(B(O)O)c1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccnc1-c1cc(Br)cc(C=O)c1

Procedure:
A mixture of 1.14 g (5 mmoles) of 3-bromo-5-formyl-phenylboronic acid, 1.715 g (10 mmoles) of methyl 2-chloro-nicotinate, 100 mg of tetrakis-(triphenyl phosphine)palladium, 2.5 mL of ethanol, 10 mL of 2M sodium bicarbonate solution, and 10 mL of toluene was heated 20 hrs at 80° under nitrogen. After diluting with ethyl acetate, the reaction mixture was washed with saturated NaCl solution. The organic phase was dried over anhydrous MgSO4. Solvent removal gave a crude product which was purified on silica using ethyl acetate:hexane mixture as solvent to give the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23]C)=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].C(O)C.[OH-].[K+:29]>O>[C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23][K:29])=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: [K+]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O[K])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 40 °C
Reaction time: 6 h

Procedure:
CF3O(CF2)3OCHFCF2COOCH3 (19.6 grams, 50.0 mmol), 15 grams of ethanol, 2.8 grams (50 mmol) of potassium hydroxide, and 2 grams of water were added to a 100-mL, 3-necked flask, equipped with a stirrer, a condenser, and a thermometer. The reaction mixture was heated on a heating mantle and stirred for 6 hours at 40° C. A clear, colorless solution of CF3O(CF2)3OCHFCF2COOK was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([Cl:25])=[CH:18][C:17]=3[Cl:26])=O)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]([Cl:26])[C:16]2[N:15]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:27]([F:29])([F:28])[F:30])[CH:11]=3)[O:23][C:22](=[O:24])[C:21]=2[CH:20]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cc(Cl)cc12
Temperature: 55 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a solution of 2-(3-chloro-2-pyridyl)-N-[2,4-dichloro-6-hydroxycarbonyl-phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (18.4 g, 38.3 mmol) in methylene chloride (130 mL) was added acetic anhydride (39.4 mL, 417 mmol). The reaction was then heated to 55° C. for 2 h and then stirred for a further 16 h at room temperature. The resulting solid was filtered and washed with cold methylene chloride. Trituration with diethyl ether afforded the title compound (10.1 g, 57%).
Reaction SMILES: [BrH:1].C(Cl)(Cl)=S.Br[C:7]1[C:16]([N:17]=[C:18]=[S:19])=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[CH:10][CH:11]=[N:12]2>O>[Br:1][C:16]1([N:17]=[C:18]=[S:19])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[CH2:7]1
Reactant: Br
Reactant: S=C=Nc1ccc2nccnc2c1Br
Agent: S=C(Cl)Cl
Solvent: O
Product: S=C=NC1(Br)C=Cc2nccnc2C1
Reaction time: 2 h
Yield: 90 %

Procedure:
The crude hydrobromide product described above (4.27 g, 14.0 mmol) was dissolved in 60 ml of water; thiophosgene (Aldrich, 1.28 ml, 16.8 mmol) was added in small portions with vigorous stirring. After 2 hours, the red color of the solution was discharged. The solid formed was filtered off and washed thoroughly with water. After drying in vacuo at 25° C., 3.38 g of brick red crystals were obtained, m.p. 157-8° C., representing a yield of 90%. A portion of this material was further purified by column chromatography to give white crystals, m.p. 157-8° C. Using various analytical procedures, these crystals were determined to be 5-bromo-6-isothiocyanatoquinoxaline.
Reaction SMILES: BrC1N(C)C=NC=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C=C(NS(C)(=O)=O)C(OC)=C(NC(=O)C2C=CC(C)=C(N3[CH:40]=[C:39]([C:41]4[N:42]([CH3:50])[C:43](C(O)(C)C)=[N:44][CH:45]=4)N=N3)C=2)C=1)(C)(C)C>>[C:39]([C:41]1[N:42]([CH3:50])[C:43]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])=[N:44][CH:45]=1)#[CH:40]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(C)(C)O)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cn1cncc1Br
Product: C#Cc1cnc(C(=O)c2ccccc2)n1C

Procedure:
(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone was prepared from 5-bromo-1-methyl imidazole and benzoyl chloride in the same manner as 1-methyl-5-ethynyl-1H-imidazole-2-carboxylic acid ethyl ester (Example 27).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(N=C3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1ccc(S(=O)(=O)N2CCN(NC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
1-[1-(4-Pyridyl)-4-piperidinylideneamino]-4-(4-vinylphenylsulfonyl)-2-piperazinone (200 mg) was dissolved in methanol (10 ml), combined with acetic acid (110 mg) with cooling on ice followed by sodium cyanoborohydride (57 mg), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (150 mg) as a colorless amorphous material.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[O:10][CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=[CH2:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[O:10][CH2:9][CH2:8]1
Reactant: CCCCCC(=O)c1ccc2c(c1)OCCC2(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CCCCC)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl triphenylphosphonium bromide (1.062 g, 2.97 mmole) in 20 mL of THF at 0° C. was treated dropwise with 1.2 mL of a 2.5M butyllithium solution. The mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. A solution of 1-(4,4-dimethyl-chroman-7-yl)-hexan-1-one (0.516 g, 1.98 mmole) in 5 mL of THF was added to the ylide solution. The reaction mixture was stirred at room temperature for one hour, quenched by the addition of 25 mL water and extracted with three 25 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The product was purified by flash chromatography (SiO2, 2% ethyl acetate in hexanes) to yield 0.442 g of 4,4-dimethyl-7-(1-methylene-hexyl)-chroman as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]([CH2:30][C:31]3[CH:32]=[C:33]4[C:48]([CH3:49])=[N:47][N:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:34]4=[N:35][C:36]=3[N:37]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:12][CH:13]=2)=[N:4]1.[CH3:54]I.O>CN(C=O)C>[F:27][C:26]([F:28])([F:29])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][N:14]([CH2:30][C:31]1[CH:32]=[C:33]2[C:48]([CH3:49])=[N:47][N:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:34]2=[N:35][C:36]=1[N:37]([CH2:42][CH:43]1[CH2:45][CH2:44]1)[CH2:38][CH:39]1[CH2:41][CH2:40]1)[C:11]1[N:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][N:3]([CH3:54])[N:4]=2)=[CH:13][N:12]=1
Reactant: CI
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(-c4cc[nH]n4)cn3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(-c4ccn(C)n4)cn3)cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.008 g, 0.21 mmol) in DMF (2 ml) was added dropwise with stirring to 5-(((5-(1H-pyrazol-3-yl)pyrimidin-2-yl)(3,5-bis(trifluoromethyl)benzyl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine, obtained in Example 8 (0.03 g, 0.042 mmol). The reaction mixture was stirred for 20 min at 0° C. CH3I was added at this temperature and the mixture was stirred for an hour at 20-35° C. The reaction mixture was then treated with water and the mixture was extracted three times with ethyl acetate (50 ml). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get the crude product. The crude product was further purified by column chromatography using 60-120 silica gel and 35% EtOAc in petroleum ether as eluent to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:27])[F:29])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCNC2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC[C@@H](n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 104 %

Procedure:
Combine 4-[(R)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1-piperidin-3-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.49 mmol; 741 mg); formaldehyde (5 equiv; 7.46 mmol; 560 μL); sodium triacetoxyborohydride (2 equiv; 2.98 mmol; 632 mg) and THF (25 mL) and stir at 20° C. for 20 min. Dilute with EA, wash the organic phase 2× with saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate to provide the title compound (790.3 mg; 1.55 mmol; 104%). MS (ES+): m/z=511 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[C:38]([Cl:40])[CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:36]2[CH:35]=[C:34]([Cl:33])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 3.6 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3,5-dichloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (2.7 mg, 3.6%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[I-].[Mg+2].[I-].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:25][CH3:26])=[C:16]([CH:18]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]2=[O:24])[CH:17]=1>ClCCl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:25][CH3:26])=[C:16]([CH:18]2[C:22](=[O:23])[CH:21]3[CH:20]([C:2]4([CH3:1])[O:3][C:4]3([CH3:7])[CH:5]=[CH:6]4)[C:19]2=[O:24])[CH:17]=1
Reactant: Cc1ccc(C)o1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)C=CC2(C)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-Dimethylfuran (2.3 ml, 21.6 mmol) and magnesium iodide (0.40 g, 1.4 mmol) are added to a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (2.0 g, 7.2 mmol) in dichloromethane (10 ml) and the mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:12]3[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 410.1 [(M−H)−]; mp 306° C.