Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].S(=O)(=O)(O)O>O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH:12]([C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(CSc1nc2ccccc2[nH]1)C(=O)O
Yield: 105.5 %

Procedure:
47.4 g of 2-mercaptobenzimidazole and 40.7 g of itaconic acid, mixed in finely powdered form, are introduced into 150 ml of 70% aqueous sulfuric acid in the course of 1 hour. The temperature is kept at 40° to 43°, with stirring. The mixture is then allowed to react completely at the above temperature over a period of 11/2 hours and the reaction mixture is diluted with water and ice to about 2 liters. The product is precipitated by addition of 30% aqueous sodium hydroxide solution to pH 4 and filtered off. After washing with water and drying in vacuo at about 30°, 92.5 g of 3-(benzimidazol-2-ylthio)-propane-1,2-dicarboxylic acid are obtained in the form of a dihydrate of melting point 113° (decomposition), corresponding to 97% of theory.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][CH2:11]/[C:12](=[CH:14]/[CH2:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])\[CH3:19])/[CH3:13])/[CH3:8])[CH3:3]>[Ni].C(CC(C)(C)C)(C)C.[H][H]>[CH3:30][CH:28]([CH2:27][CH2:26][CH2:25][CH:23]([CH2:22][CH2:21][CH2:20][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:19])[CH3:24])[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)CC(C)(C)C
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
A tubular reactor of 2.0 cm in inner diameter and 10 cm in length was packed with 20 g of carrier-supported nickel catalyst. Hydrogenation was carried out by feeding into the reactor the 50 wt % squalene solution in isooctane and hydrogen gas to obtain a squalane solution in isooctane. Samples were taken out for 30 hours after the temperature was stabilized at 210° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)CCCC>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH2:3][CH2:2][CH2:1][CH2:6][CH3:5])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 40.2 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of n-pentanol are treated in the same manner as described in Example 13. One g of n-pentyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 40.2%
Reaction SMILES: [C:1]([NH:11][CH:12]1[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][N:11]([CH:12]1[CH2:14][CH2:13]1)[C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CI
Reactant: O=C(NC1CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CC1

Procedure:
The synthesis of N-carbobenzyloxy cyclopropylamine is carried out according to the method outlined in J. Heterocycl. Chem (1983), 1035, using N-carbobenzyloxy cyclopropylamine (14a)(10.5 g, 0.055M) in DMF (80 ml), sodium hydride(1.4 g) and methyl iodide (4 ml). The product is purified by vacuum distillation. Bp 86-92° C., 0.02 Torr.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-]=[N+]=[N-].[Na+].Br[C:19]1[CH:20]=[CH:21][C:22]([F:46])=[C:23]([C@:25]2([CH2:44][F:45])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:26]2)[CH:24]=1.C[NH:48][C@@H]1CCCC[C@H]1NC.[BH4-].[Na+]>[Cu]I.O>[NH2:48][C:19]1[CH:20]=[CH:21][C:22]([F:46])=[C:23]([C@:25]2([CH2:44][F:45])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:26]2)[CH:24]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [BH4-]
Solvent: O
Product: Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A sealable vial was charged with (+)-sodium L-ascorbate (0.048 g, 0.241 mmol, Arcos Organics), sodium azide (0.470 g, 7.20 mmol, Aldrich), copper(I) iodide (0.138 g, 0.723 mmol, Aldrich), and N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.15 g, 2.41 mmol, step 8). The sealed vial was evacuated and backfilled with nitrogen gas. EtOH (5.62 ml) was added followed by water (2.41 ml) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.069 g, 0.482 mmol). The reaction was stirred in a pre-heated 80° C. oil bath for 16 hours. The reaction mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was taken up in MeOH (20 mL) and sodium borohydride (0.091 g, 2.41 mmol, Aldrich) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with water and further diluted with water and EtOAc. The organic layer was washed three times with a solution of aqueous saturated ammonium hydroxide and aqueous saturated ammonium chloride solution (1:9), and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a grey oil, which was used without further purification assuming theoretical yield. MS m/z=413.9 [M+H]+. Calculated for C19H16F5N3O2: 413.341.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2]>[OH-].[K+].OCC(CO)O>[C:1]([O:4][CH2:5][CH:5]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:4][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: COC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: CC(=O)OCC(COC(C)=O)OC(C)=O

Procedure:
Glycerine triacetate was prepared by the reaction of crude glycerine obtained in stage (2) with methyl acetate in the presence of potassium hydroxide as a catalyst, according to the procedure described by E. Fischer, B.53, 1640 (1920).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C1(N)C2C(=CC=CC=2)C=CC=1.[CH3:24][C:25](=[CH:27][CH2:28][CH2:29][CH:30]([CH2:32][CH:33]=O)[CH3:31])[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:33]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:32][CH:30]([CH2:29][CH2:28][CH:27]=[C:25]([CH3:26])[CH3:24])[CH3:31]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: Nc1cccc2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCCC(C)CCNc1cccc2ccccc12
Reaction time: 0.08 h
Yield: 21 %

Procedure:
2.0 g α-naphthylamine (14 mmol) and 0.01 gm α-naphthylamine-HCl were added to 25 ml absolute methanol along with 2.15 gm citronellal (14 mmol) and stirred for five minutes, after which the solution turned hazy. Then 0.53 gm (8.4 mmol) sodium cyanoborohydride was added and a brief exotherm occurred. The mixture was stirred overnight at room temperature. The bottom organic layer was separated from the top aqueous layer. An IR spectra of the organic layer (a brown oil) showed no carbonyl group and very little absorption in the OH/NH region (330-360 nm). Upon vacuum distillation of the organic layer the component having a bp of 175°-180° C. was collected. The desired product was recovered as a pale yellow oil in 21% yield. The structure of the amine product was confirmed by NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](=[O:16])[N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1
Reactant: O=c1ccc([N+](=O)[O-])cn1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(=O)n(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
To a suspension of 5-nitro-1-phenyl-1H-pyridin-2-one (60 mg, 0.28 mmol) in ethyl acetate (2 mL) and ethanol (2 mL) was added 5% Pd—C (10 mg), the resulting mixture was stirred under hydrogen atmosphere for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated to give the title compound as a green oil. The product was used to next step without further purification. LC-MS (ES, Pos.): 187 [MH+], and 1H NMR (CDCl3, 400 MHz): δ=3.09 (br s, 2H), 6.60 (d, J=9.6 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 7.12 (dd, J=9.6, 3.0 Hz, 1H), 7.37-7.41 (m, 3H), 7.45-7.49 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:24]=C1C2C3SC4=CCCC=C4C=C(C(OC)=O)C=3C=CC=2CC1>>[O:24]=[S:14]1[C:8]2[CH:7]=[CH:6][C:5]3[CH2:4][CH2:3][C:2](=[O:1])[C:23]=3[C:9]=2[CH2:10][CH2:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(=O)CC3
Reactant: COC(=O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccc3c(c1CC2)C(=O)CC3

Procedure:
Substituting an equivalent amount of methyl 1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-carboxylate in Example 38, Step A, in place of methyl 1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]-indeno[5,4-f]thiepin-6-carboxylate and taking the product through Step B of this example provided the title compound.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][S:23][C:24]2[CH:25]=[C:26]([O:32]C)[C:27]([O:30]C)=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][S:23][C:24]2[CH:25]=[C:26]([OH:32])[C:27](=[O:30])[NH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: COc1cc(SCc2ccc(F)cc2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccc(F)cc2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 5-(4-fluorobenzylthio)-2,3-dimethoxypyridine (Intermediate 14).
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.[ClH:53]>O1CCOCC1>[ClH:53].[NH2:19][C@@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:2]([OH:1])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 2 h

Procedure:
To a solution of 5.0 g (13 mmol) of tert-butyl (1S)-1-{(1SR)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate in 15 mL of dioxane was added 20 mL of 4M hydrochloric acid in dioxane. The reaction mixture was stirred for 2 h and concentrated under reduced pressure to leave 4.2 g (>99) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride. 1H-NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.10–7.92 (m, 5H), 7.79–7.65 (m, 2H), 3.86 (s, 1H), 3.16-2.91 (m 3H), 1.58–1.33 (m, 2H), 1.20 (m, 4H), 0.84 (m, 3H); ES-LCMS m/z 288 (M+H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][N:5]=1.C([Li])CCC.CCCCCC.[CH2:31]=[O:32]>C1COCC1.CCOCC>[C:13]1([C:7]2[O:6][N:5]=[C:4]([C:3]#[C:2][CH2:31][OH:32])[C:8]=2[C:9]([F:12])([F:11])[F:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: FC(F)(F)c1c(C=C(Br)Br)noc1-c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 62.6 %

Procedure:
To a solution of 3-(2,2-dibromovinyl)-5-phenyl-4-(trifluoromethyl)isoxazole (Preparation 62A, 0.496 g, 1.19 mmol) in THF (6.0 mL) at −78° C. was slowly added a 2.5 M solution of butyl lithium in hexane (1.05 mL, 2.61 mmol). The reaction mixture was stirred at −78° C. for 25 min. and then warmed to room temperature gently with a heat gun. Once at room temperature, paraformaldehyde (0.713 g, 23.74 mmol) was added, and the reaction mixture was stirred for 5 min. The mixture was diluted with ether, washed with water (2×), and washed with brine. The combined aqueous layers were extracted with ether, and the combined organics layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1%-5%-20%) to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-yn-1-ol (0.199 g, 0.745 mmol, 63% yield) as a yellowish-orange solid. The product had an HPLC ret. time=2.39 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=268.17.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:19]([C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC1(C(=O)OC)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10.0 g (0.042 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 100 mL of tetrahydrofuran and combined batchwise with 5.16 g (0.044 mol) of potassium tert-butoxide while cooling. Then at about 18° C. to 22° C., 6.296 mL (0.083 mol) of bromoethane are added dropwise; after it has all been added, the mixture is stirred for about 1.5 hours at ambient temperature. The precipitate formed is suction filtered and the solvent is removed by distillation. The residue remaining is taken up in diethyl ether and extracted with water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product obtained is used in the next step without any further purification. Yield: 7.92 g of yellow oil (70% of theoretical yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
228 Grams of crude ethyl 1-benzyl-3,4-diphenylpyrazole-5-carboxylate (prepared as described below) dissolved in 3200 ml of anhydrous diethyl ether are added, at 0°C and under a nitrogen atmosphere, to 47 grams of lithium aluminium hydride suspended in 1600 ml of anhydrous diethyl ether. The solution is stirred overnight at ambient temperature and then cooled to 0° C, whereupon 55 ml of water, 20.2 ml of 10N soda and 83 ml of water are slowly and successively added under a nitrogen atmosphere, and the resulting precipitate is filtered. The filtrate is evaporated under reduced pressure and the residue is dissolved in 360 ml of di-isopropyl ether. 1 -Benzyl-3,4-diphenyl-5-hydroxymethylpyrazole melting at 138° C is thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1
Product: Nc1ncc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.81) (0.20 g, 0.45 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.109 g, 0.49 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.160 g, 77%). MS (ISP) 461.2 [(M+H)+]; mp 260° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[OH-].[Na+].Cl>O.CCO.O.CCO>[CH3:4][C:3]1[C:2]([OH:1])=[CH:13][C:12]2[CH:11]=[N:10][C:9]([S:15][CH3:16])=[N:8][C:7]=2[N:6]=1
Reactant: CC(=O)CO
Reactant: CSc1ncc(C=O)c(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc2cc(O)c(C)nc2n1
Yield: 55.4 %

Procedure:
Add 1-hydroxypropan-2-one (24.3 mL, 355 mmol) and 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (50 g, 296 mmol) to a solution of sodium hydroxide (23.64 g, 591 mmol) and water (200 mL). Add EtOH (600 mL) to the suspension and stir at RT overnight. Slowly add a solution of concentrated HCl (50 mL) in water (350 mL). Add 1:1 EtOH/H2O (100 mL) and collect the solids by filtration. Wash the solids with 1:1 EtOH/H2O (250 mL), ice cold EtOH (4×25 mL) and hexanes (2×250 mL). Dry in the vacuum oven at 30-35° C. to provide the title compound as a tan solid (34 g, 56% yield). MS (m/z): 208.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[C:15]1[C:16]2[N:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1.CCN(CC)CC.Cl>CN(C=O)C.O>[CH3:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][NH:2][C:15]1[C:16]2[N:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Cc1cc(O)ccc1OCCN
Reactant: Clc1ncnc2scnc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(O)ccc1OCCNc1ncnc2scnc12
Reaction time: 24 h
Yield: 28.7 %

Procedure:
4-(2-Aminoethoxy)-3-methylphenol hydrochloride (0.30 g, 1.5 mmol), 7-chlorothiazolo[5,4-d]pyrimidine (0.25 g, 1.5 mmol), and Et3N (300 mg, 3 mmol) were dissolved with magnetic stirring in DMF (6 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. After 24 h, the reaction mixture was diluted with H2O (120 mL), and treated with 2 N HCl to adjust the pH to 5. After 24 h, a dark yellow solid precipitated and was removed by filtration. The filtrate was extracted with EtOAc (2×50 mL), and the pooled organic fractions were filtered and concentrated in vacuo to afford 3-methyl-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethoxy]-phenol (Compound 22; 0.13 g) as a yellow powder, which was used without further purification in the next step: ESIMS m/z 303.0 ([M+H]+).
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([C@@H:23]([C:31]3[CH:39]=[CH:38][C:34]([CH:35]=[N:36]O)=[CH:33][CH:32]=3)[CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11][CH2:10]1.O>C(#N)C>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([C@@H:23]([C:31]3[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:38][CH:39]=3)[CH2:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=NO)cc2)cc1OC1CCCC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C#N)cc2)cc1OC1CCCC1
Yield: 87.8 %

Procedure:
Trichloromethyl chloroformate (0.18 mL, 1.5 mmol) was added to a 0° C. solution of (R)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzaldehyde oxime from Example 3 (425 mg, 1.0 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at room temperature for 1 hour before water was added. The mixture was then extracted with EtOAc. The organic phase was washed with 5% aqueous NaHCO3, water and brine, dried (MgSO4) and evaporated to afford the title compound as an off-white solid (350 mg, 86%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.O.[NH2:14][NH2:15]>C(O)C>[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([NH:14][NH2:15])=[O:2])#[N:11]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 3-cyano-benzoic acid methyl ester (2 g, 12 mmol) and hydrazine monohydrate (0.60 mL, 12 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and then the residue was triturated with diethyl ether to afford 3-cyano-benzoic acid hydrazide (1.02 g, 51%, pink solid). 1H NMR (DMSO) □ (ppm): 10.31 (s, 1H), 8.21 (m, 1H), 8.11 (m, 1H), 7.99 (m, 1H), 7.70 (m, 1H), 4.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:21])([F:23])[F:22])[CH:14]=3)=[CH:11][C:10]([C:24]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(C(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 77A in analogy to the synthesis of the compound of Example 1. 28 mg (74% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[CH2:10][S:11][C:12]2[NH:13][N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[CH2:10][S:11]([C:12]2[NH:13][N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CSc1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CS(=O)c1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a dichloromethane solution (2 mL) of N-(3-chloro-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide (0.080 g, 0.25 mmol), m-chloroperbenzoic acid (0.25 mmol) was and the mixture was stirred for 2 h. The reaction mixture was quenched with sodium bicarbonate solution and the product extracted in ethyl acetate. The ethyl acetate layer was dried, filtered and evaporated to afford crude residue. This residue was purified by reverse phase HPLC to afford pure title compound (40 mg, 45%). MS (ES) 361.5