Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:18]1([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:29]([OH:32])[OH:30])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 300-mL three-neck flask was placed 5.0 g (13 mmol) of 2-(4-bromophenyl)-3-phenylquinoxaline, and the atmosphere in the flask was replaced with nitrogen. There was added 40 mL of tetrahydrofuran, and the mixture was cooled to −78° C. under a nitrogen stream. After the cooling, 10 mL (16 mmol) of 1.6 M n-butyllithium was dripped thereinto, and the mixture was stirred at the same temperature for 1 hour. After a predetermined time, 3.1 mL (27 mmol) of trimethyl borate was added thereto, and the temperature of the reaction solution was raised to room temperature, and then, the solution was stirred for 10 hours. After a predetermined time, the reaction solution was cooled to 0° C., to which 100 mL of 0.1 M hydrochloric acid was added, and the solution was stirred for 1 hour. After a predetermined time, an organic substance was extracted with ethyl acetate from the aqueous phase. The extracted solution combined with the organic phase was washed with brine, and then dried with magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was concentrated to give a solid. The solid was recrystallized with ethyl acetate/hexane; thus, 3.0 g of a pale-yellow powder which was a product was obtained in a yield of 66%.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=3)([C:3]#[N:4])[CH3:20])[N:7]=2)[CH:11]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(C(F)(F)F)cc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 19, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.45 g, 90%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=508. 1H NMR: (400 MHz, DMSO-d6): 1.77 (s, 3H), 5.49-5.65 (m, 2H), 7.84-7.93 (m, 5H), 8.56 (d, J=1.1 Hz, 1H) and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.09 (s, 3F) and −42.03 (s, 3F).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:11][C:4]1[CH:3]=[C:2]([CH:12]=[CH2:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h
Yield: 343 %

Procedure:
4-Bromo-2-fluoro-1-nitro-benzene (691 mg, 3.14 mmol), tributyl-vinyl-stannane (1.2 g, 3.77 mmol), triphenylphospine (49 mg, 0.19 mmol) and tetrakistriphenylphosphinpalladium(0) (73 mg, 0.06 mmol) were dissolved in toluene (25 ml) and stirred for 5 hours at reflux. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 ml) and diethyl ether (50 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an oil (1.8 g). The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-5%). Fractions containing the product were combined and the solvent evaporated to give an oil (360 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20](O)=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:48]1([NH:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:55]1([N:54]([CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[C:20](=[O:21])[CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[CH3:23])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)N(C1CCCCC1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a flask was added 0.180 g (0.5 mmol) of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, 1.8 mL of anhydrous dichloromethane, 0.194 g (0.6 mmol) of TBTU (o-benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium tetrafluoroborate), 0.066 mL (0.6 mmol) of dicyclohexylamine and finally 0.22 mL (1.26 mmol) of diisopropylethyl amine. The reaction was stirred at room temperature for 20 hr then diluted with more dichloromethane (10 mL). The solution was washed with dilute aqueous citric acid (2×10 mL), aqueous sodium bicarbonate (10 mL) and water (10 mL) before drying (MgSO4), filtering and evaporating the filtrate. The residue was slurried with a hexanes/ethyl acetate mix to give the title compound. 1H NMR (CDCl3) δ 7.56 (2H, d), 7.40 (2H, d), 7.01 (1H, bs), 6.61 (1H, d), 6.56 (1H, dd), 3.75 (3H, s), 3.63 (2H, s), 3.41 (1H, m), 2.73 (1H, b), 2.38 (3H, s), 0.9-1.8 (20H, m) Mass Spectrum m/e 521/523 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:6]=1C(O)=O>S([O-])([O-])(=O)=O.[Cu+2].N1C2C(=CC=CC=2)C=CC=1>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: Cc1occ(C(F)(F)F)c1C(=O)O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(C(F)(F)F)co1
Yield: 59.6 %

Procedure:
13.45 g of the product obtained in Stage C were heated at 240° C. for 30 minutes in the presence of 0.6 g of copper (II) sulfate and 10 ml of quinoline. The reaction mixture was dried and distilled under atmospheric pressure to obtain 6.2 g of the expected product with a boiling point of 72°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Br[CH2:13][C:14]([O:16][CH2:17]C)=[O:15]>[Li+].C[Si]([N-][Si](C)(C)C)(C)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[C:6]1=[O:11]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(Br)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)CC1Cc2c(Br)cccc2C1=O
Temperature: 0 °C
Yield: 91.8 %

Procedure:
To a solution of 4-bromoindanone (15.8 g, 75 mmol) at −78° C. was added LiHMDS (1 M in THF, 90 mL). The slight brown solution was allowed to warm up to 0° C., and was cooled again to −75° and ethyl 2-bromoacetate (9.1 mL, 82 mmol) was added dropwise. The mixture was allowed to warm up over night (−75° C. to −20° C. over 12 h). The mixture was quenched with sat. ammonium chloride and was extracted with ethyl acetate. Flash chromatography give 19.5 g of the title compound in a mixture with the starting indanone ethyl 2-[4-bromo-2-(2-ethoxy-2-oxo-ethyl)-1-oxo-indan-2-yl]acetate H9 and which was used without further purification for the next step (purity, 60% of the desired product).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:10]([S:8][C:7]1[C:2]([Br:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: SCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzylmercaptan and DBU in dioxane. EI-MS m/e (%): 363 (M{81Br}+, 48), 361 (M{79Br}+, 46), 282 ([M—Br]+, 68), 249 (35), 91 (100).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH:6]=[CH:5][C:4]2=[O:21].[C-:22]#[C-:23].[Li+].[Li+]>>[CH3:1][CH2:2][C@@:3]12[C@:4]([OH:21])([C:22]#[CH:23])[CH:5]=[CH:6][C@H:7]1[C@@H:8]1[CH2:9][CH2:10][C:11]3[C@@H:16]([C@H:17]1[CH2:18][CH2:19]2)[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=3
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Reactant: [C-]#[C-]
Agent: [Li+]
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Yield: 75 %

Procedure:
By treating 18-methyl-4,15-estradiene-3,17-dione (Formula III: Y=O, A-B=CH=CH) with lithium acetylide, gestodene is obtained in a high yield of about 75%. However, this method is usable only for amounts of starting material compounds up to 100 g; ethynylation in this manner therefore cannot be performed on an industrial scale. Moreover, it has been found that the 18-methyl-4,15-estradiene-3,17-dione starting material can have a sensitizing effect in case of skin contact, consequently protective measures must be observed when handling 18-methyl-4,15-estradiene-3,17-dione.
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)=[N:4][N:3]=1.Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[C:31]#[N:32]>>[C:31]([C:30]1[CH:33]=[C:26]([CH:27]=[CH:28][C:29]=1[O:34][CH3:35])[CH2:25][S:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1)#[N:32]
Reactant: COc1ccc(CCl)cc1C#N
Reactant: O=C(CCc1ccccc1)Nc1cc(-c2nnc(S)o2)ccn1
Product: COc1ccc(CSc2nnc(-c3ccnc(NC(=O)CCc4ccccc4)c3)o2)cc1C#N
Yield: 39 %

Procedure:
In the same manner as in Example 1 and using N-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]-3-phenylpropionamide instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 39%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[OH-].[O-:15]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:15])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a suspension of 6-chloro-3-nitropicolinonitrile (2.54 g, 13.8 mmol) in water (27.0 mL) was added NH4OH (5.61 mL, 36.0 mmol) at room temperature. After stirring for 20 min at room temperature, Na2S2O4 (13.7 g, 79.0 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was filtered, and washed with water. The filtercake was dried under vacuum to give 3-amino-6-chloropicolinamide (1.67 g, 70%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.36 (1H, brs), 6.00 (2H, brs), 7.00 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz), 7.63 (1H, brs).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:8].[CH3:19][N:20]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]1[C:28](Cl)=[O:29]>CO.C(Cl)Cl.[Pd]>[CH3:17][N:10]1[CH:11]=[C:12]([NH:14][C:28]([C:21]2[N:20]([CH3:19])[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=2)=[O:29])[CH:13]=[C:9]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])=[O:8]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: CN(C)CCCNC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
N-[3-(Dimethylamino)propyl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (0.241 g, 0.95 mmol; see step (i) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (55 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.179 g 0.95 mmol; see Preparation 1(ii) above) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound (0.239 g, 67%).
Reaction SMILES: [CH2:1](N(CC)C1C=CC=CC=1)C.[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#C)=[CH:17][C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:18]2[O:19][C:20]([CH3:21])=[CH:1][C:17]=2[C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C#CCOc1cc(-c2cn(C)c(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(-c3cn(C)c(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1
Temperature: 190 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To 50 ml of N,N-diethylaniline, 0.64 g (1.8 mmol) of 5-(4-chloro-2-fluoro-5-propargyloxyphenyl)-1-methyl-2-trifluoromethyl-4(1H)-pyridone and 0.56 g (3.7 mmol) of cesium fluoride were added, and the mixture was stirred at from 180 to 200° C. for 2.5 hours. This reaction solution was poured into water and extracted with ethyl acetate. After washing with concentrated hydrochloric acid, water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 75%) of the desired product. Melting point: 208-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[I:17]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: ClI
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1, 15.00 g, 98.31 mmol) in 300 mL of dichloromethane under an atmosphere or nitrogen, pyridine (7.951 mL, 98.31 mmol) and iodine monochloride (110 mL, 1.0 M in dichloromethane, 110 mmol) are added slowly over 20 minutes. The reaction is stirred at room temperature for 2 hours, then quenched with 100 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers are separated, solids collected from the aqueous layer by filtration and combined with the organic layer. The aqueous layer is extracted with ethyl acetate, and the organic layers are combined and washed with brine, then concentrated under vacuum. The resulting solid is washed with 20% ethyl acetate in hexane to provide the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][Br:13])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(Br)nc1CBr
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A mixture of 2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (5.67 g, 22.68 mmole), N-bromosuccinimide (4.44 g, 24.95 mmole) and benzoyl peroxide (275 mg, 1.13 mmole) in carbon tetrachloride (25 ml) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a white solid (4.46 g): MS: (+) m/z 337.80, 329.93, 331.93 (M+1, 79Br/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[S:29]>O1CCCC1>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28](=[S:29])[NH:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[C:3]=1[NH:9][CH2:10][C:11]([F:17])([F:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(F)(F)CNc1c(N)cccc1N
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[(2,6-diaminophenyl)amino]-2,2-difluoropropanoate (998.3 mg, 3.851 mmol) in tetrahydrofuran (20 mL) was added a solution of 2,4-dichlorophenyl isothiocyanate (785.9 mg, 3.851 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 1 hr and warmed to room temperature and stirred for 2 hrs. After removal of solvent, the residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (1.61 g, 3.486 mmol, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[C:11]1([C@H:17](O)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: C[C@@H](O)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn([C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 20 mL microwave vial was charged with 1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 7.1 mmol), (R)-1-phenylethanol (1.31 mL, 10.7 mmol), triphenylphosphine (3 g, 11.4 mmol) and tetrahydrofuran (15 mL). The reaction was stirred at ambient temperature for 10 minutes before adding diisopropyl azodicarboxylate (2.25 mL, 11.14 mmol) with cooling. The vial was heated under microwave irradiation at 140° C. for 15 mins. After cooling, the solvent was removed in vacuo and the residue purified by flash chromatography on SiO2 with hexane—30% ethyl acetate/hexane (gradient) to afford intermediate (6f), 1((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester as an oil, 1.646 g, 94%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[C:12]1([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:19][CH2:20][C@@H:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:19][CH2:20][C@@H:21]([NH:26][C:9]([C@H:7]2[O:8][C@@H:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: CC(C)C[C@H](N)COC(c1ccccc1)c1ccccc1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COC(c1ccccc1)c1ccccc1)CC(C)C

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid and 1-(S)-(diphenylmethoxy)methyl-3-methylbutylamine (its preparation is described in the after-mentioned Reference Example 3), to prepare the titled compound
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)CCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCc1ccccc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
250 g (1.4 mols) of 5-phenylvaleric acid are dissolved in 450 ml of absolute ethanol. 114 ml of concentrated sulphuric acid are added to the clear colourless solution and the reaction mixture is refluxed for 48 hours. The reaction mixture, which initially is two-phase, becomes almost homogeneous and separates into two phases again on cooling. The cold two-phase reaction mixture is poured onto diethyl ether and about 1 kg of ice. The aqueous phase is extracted with ether twice more. The ether phases are washed twice with 2 N sodium carbonate solution and twice with NaCl solution. The combined ether phases are dried over MgSO4 and the solvent is removed on a rotary evaporator. After drying under a high vacuum at room temperature, 281.7 g of a colourless oil (97.5% of theory) are obtained.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:5]([N:8]2[CH2:13][CH2:12][C:11]3([CH2:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14]3)[CH2:10][CH2:9]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(C1CCC1)N1CCC2(CC1)Cc1ccccc1O2

Procedure:
A mixture of 4.2 g of cyclobutylcarbonyl chloride in 10 ml of chloroform is added dropwise to a stirred mixture of 6.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 20.0 g of potassium carbonate in 75 ml of chloroform. After total addition, the reaction mixture is successively refluxed for 24 hours, cooled, filtered and poured into water. The biphasic mixture is sequentially washed with 3 N hydrochloric acid, 3 N sodium hydroxide, a saturated sodium chloride solution, dried and the solvent is removed, leaving a solid residue. The residue is recrystallized twice from a benzene-hexane mixture to give the product, 2,3-dihydro-1'-cyclobutylcarbonylspiro[benzofuran-2,4'-piperidine], mp 91°-93° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17]O)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2.[S:19](=O)(=[O:22])([OH:21])[OH:20]>>[NH2:1][C:2]1[N:3]([CH2:16][CH2:17][S:19]([OH:22])(=[O:21])=[O:20])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2
Reactant: CC(C)(C)c1nc2nn(CCO)c(N)c2c(=O)[nH]1
Reactant: O=S(=O)(O)O
Product: CC(C)(C)c1nc2nn(CCS(=O)(=O)O)c(N)c2c(=O)[nH]1
Reaction time: 3 h

Procedure:
3-Amino-2-(2-hydroxyethyl)-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (5 g) prepared as in Example 52 was added to concentrated sulphuric acid (10 ml). The solution was kept at 130°-135° C. for 3 hours, then cooled and poured onto ice (30 g). The precipitate which formed was filtered off, water washed and dissolved in 2 M sodium hydroxide solution. A trace of solid was filtered off, and the filtrate was acidified with concentrated hydrochloric acid to re-precipitate the title compound (4.4 g), m.p. 307°-309° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Reactant: CCCN
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C1CCOC1

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 181 mg of the product obtained in Stage 1 of Example 2 and 3 ml of butanol and using 0.062 ml of 1-propanamine in place of the benzylamine. In this way 136 mg of expected product is obtained in the form of beige crystals.