Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=NC(C(F)(F)F)=C[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.I[C:60]1C=CC=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:60][CH:61]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-iodo-3-(trifluoromethyl)benzene.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:29]2[C@:24]([CH3:32])([CH2:25][C@@H:26]([F:31])[C:27](=[O:30])[CH2:28]2)[C@@H:23]2[C@H:7]([C@H:8]3[C@:20]([CH3:33])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].O.C(OCC)(=O)C>C1COCC1.CO>[C:1]([O:4][C@H:5]1[CH:29]2[C@:24]([CH3:32])([CH2:25][C@@H:26]([F:31])[C@@H:27]([OH:30])[CH2:28]2)[C@@H:23]2[C@H:7]([C@H:8]3[C@:20]([CH3:33])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)C[C@@H](F)C(=O)CC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)C[C@@H](F)[C@@H](O)CC12
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a solution of the fluoroketone (3) (270 mg) in THF (24 ml) was added sodium borohydride (90 mg) in methanol (6 ml) at room temperature and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate and the excess reagent was quenched with 2N-HCl. The organic phase was washed with saturated NaHCO3 and brine, and dried over MgSO4. The crude mixture obtained upon evaporation of the solvent was separated by column chromatography on silica gel (10 g). Elution with benzene-ethyl acetate 10:1 gave 6β-acetoxy-2α-fluoro-3α-hydroxycholestane (5) 54 mg, 2%), mp 148°-150° (CHCl3 -MeOH); δ0.79(3H, s, 18-H3), 2.20(3H, s, acetyl), 4.22(1H, m, W1/2 =13 Hz, 3β-H), 4.65(1H, m, 2β-H), and 4.98(1H, m, 6α-H); m/z, 404 (M+ -AcOH), 389,384, 371 and 369.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]1[CH2:7][CH2:6]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2](=[S:26])[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]1[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=S
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (Example 38 a, 6.7 g, 29 mmol) and Lawesson's reagent (CAN 19172-47-5, 6.06 g, 15 mmol) in toluene (60 mL) was stirred at 90° C. for 2.5 h. After removal of the solvent in vacuo, the residue was purified by column chromatography (silica gel, 100 g, eluting with 5% methanol in ethyl acetate) to yield the title compound (5.1 g, 71%) as yellow solid; MS: m/e=267.1 [M+Na]+
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[N:33]=[CH:32][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=4)[CH:27]=3)[N:22](C3CCCCO3)[N:21]=2)[CH:15]=1)=[O:13].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:30]1[C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:2]3[OH:1])=[O:13])[CH:19]=[CH:18][CH:17]=2)=[N:33][CH:32]=[N:31]1
Reactant: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.9 %

Procedure:
To a stirred solution of N-((1S,2R)-2-hydroxyindanyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenyl methyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.342 g, 0.448 mmol) was added 4.0M hydrochloric acid in dioxane (10.0 mL) and the mixture stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0233 g, 12% yield). 1H NMR (CD3OD) δ 8.82 (s, 1H), 8.58 (s, 1H), 8.24 (d, 1H), 8.12 (br d, 1H), 8.00 (d, 1H), 7.01 (t, 2H), 7.37 (d, 1H), 7.30 (d, 1H), 7.24 (m, 2H), 5.63 (m, 1H), 4.74 (m, 1H), 3.26 (m, 1H), 3.05 (1H). ES-MS (m/z) 437 [M+1]+
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]([C:18]#[C:19][CH2:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]>CCO>[OH:1][CH:2]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CNC(=O)CCC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1
Solvent: CCO
Product: CNC(=O)CCCCc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Reduction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido) propyl)phenyl)-N-methylpent-4-ynamide using EtOH as the solvent yielded 5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido)propyl)phenyl)-N-methyl pentanamide as yellow oil. Yield (0.911 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.0 (bs, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.16 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 5.56 (bs, 1H), 4.83-4.86 (m, 1H), 3.54-3.60 (m, 1H), 3.37-3.44 (m, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.63 (t, J=7.6 Hz, 2H), 2.12 (t, J=7.6 Hz, 2H), 1.96-2.0 (m, 2H), 1.58-1.67 (m, 4H).
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][C@@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][N:19]2[CH3:25])C(C)=CC=1.Cl.NO.C(N(CC)CC)C>CC(O)C>[NH2:3][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][N:19]1[CH3:25]
Reactant: CO[C@@H]1C[C@@H](Cc2c[nH]c3ccc(-n4c(C)ccc4C)cc23)N(C)C1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CO[C@@H]1C[C@@H](Cc2c[nH]c3ccc(N)cc23)N(C)C1
Yield: 99.4 %

Procedure:
A mixture of 5-(2,5-dimethyl-1H-pyrrolyl)-3-[(2R,4R)-N-methyl-4-methoxypyrrolidin-2-ylmethyl]-1H-indole (2.20 g, 6.52 mmol), hydroxylamine hydrochloride (7.25 g, 104 mmol, 16 eq), and triethylamine (7.28 mL, 52.2 mmol, 8 eq) in 2-propanol (22 mL) was heated at reflux under nitrogen for 8 hours. The resulting reaction solution was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (50 mL) and a saturated solution of sodium hydrogen carbonate (50 mL). The ethyl acetate layer was removed, and the aqueous layer was extracted with methylene chloride (3×50 mL). All organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure to afford the title compound (1.68 g, 100%) as an off-white amorphous solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (CD3OD) δ7.14 (d, J=8.5 Hz, 1H), 6.99 (s, 1H), 6.94 (br s, 1H), 6.68 (br d, J=8.5 Hz, 1H), 4.90 (s, 3-NH), 3.86-3.77 (m, 1H), 3.24 (s, 3H), 3.24-3.13 (m, 2H), 2.93-2.80 (m, 1H), 2.69 (dd, J=13.7 and 9.7 Hz, 1H), 2.51 (s, 3H), 2.40-2.18 (m, 2H), 1.73-1.63 (m, 1H); 13C NMR (CD3OD) δ139.7, 133.4, 129.3, 124.4, 114.4, 112.8, 111.2, 105.5, 79.3, 68.3, 66.1, 56.7, 40.7, 39.5, 30.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].[H][H]>[Ni]>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([CH3:1])[OH:3])=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Reactant: [H][H]
Agent: [Ni]
Product: CC(=O)Oc1ccc(C(C)O)cc1
Temperature: 60 °C
Yield: 80.4 %

Procedure:
102 g of 4-acetoxyacetophenone and 10 g of Raney nickel catalyst are charged in a 300-ml stirred reactor. The reactor is then charged with hydrogen at 500 psig and heated to 60° C. for 270 minutes. The reactor is then cooled down and the product analyzed by gas chromatography. The analysis gives 80.4% 4-acetoxyphenyl methylcarbinol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[CH:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[N+:27]([O-:29])=[O:28])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2[N+](=O)[O-])c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2[N+](=O)[O-])c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with 2-nitrobenzaldehyde (59) (0.302 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 3:4 ethyl acetate/petroleum ether as the eluant to obtain 0.71 g (1.44 mmol. 72%) of 84 as a yellow oil. The oil crystallized from ether/petroleum ether to yield yellow crystalline solid: mp 130°-132° C.; IR (CH2Cl2) 3440, 2980, 1700, 1625, 1575, 1528, 1470, 1345, 1300, 1215, 1105, 905, 852, 775 cm-1 ; 1H NMR (CDCl3) δ 1.13 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H), 2.31 (s, 6H), 3.66 (s, 3H), 4.97 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.23 (s, 1H), 7.30-9.31 (m, 9H); 13C NMR (CDCl3) δ 19.98, 20.02, 22.47, 22.72, 40.34, 51.67, 67.85, 103.69, 104.37, 120.22, 121.84, 125.25, 125.61, 128.97, 129.17, 130.11, 131.01, 131.08, 134.11, 145.29, 145.82, 148.17, 149.75, 150.35, 167.43, 168.46. Anal. Calcd for C26H27N3O7 : C, 63.28; H, 5.47. Found: C, 63.18; H, 5.26.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:19])[NH2:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:19][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 4.2 %

Procedure:
A solution of the compound (710 mg, 2.56 mmol) obtained in Example 1, step 4 and ethyl bromopyruvate (0.322 mL, 2.56 mmol) in ethanol (15 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give ethyl 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (50 mg, 0.108 mmol, 64.6%) as a white powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:30])[CH:21]([CH2:22][CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:20]3)[CH:12]2[O:31][CH3:32])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pt]=O>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:30])[CH:21]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:20]3)[CH:12]2[O:31][CH3:32])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C=CCC1OC1(C)C1C(OC)C(OC(=O)NC2CCCCC2)CCC12CO2
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC1OC1(C)C1C(OC)C(OC(=O)NC2CCCCC2)CCC12CO2

Procedure:
A solution of 6-cyclohexylcarbamoyloxy-4-[3-(3-ethoxycarbonyl-2-propenyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]octane (46 mg) in ethyl acetate (30 ml) was hydrogenated under hydrogen (1 atm) in the presence of platinum oxide (5 mg) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1) to give 6-cyclohexylcarbamoyloxy-4-[3-(3-ethoxycarbonylpropyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]octane as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38]>>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:29][CH2:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: Clc1ccccc1CBr
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-2-chloro-benzene.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>COCCOC>[OH:17][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[N:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: COCCOC
Product: CC(=O)Nc1nc(C)c(-c2csc(CO)n2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200.5 mg; 0.66 mmol; 1 eq.), is dissolved in DME (7 ml) and is cooled down to −78° C. Lithium tri-tert-butoxyaluminohydride (Aldrich)(2.65 ml; 0.50 M; 1.33 mmol; 2 eq.) is added dropwise. After one hour the reduction is complete. The reaction mixture is poured on ice. The two layers are separated and the organic phase is dried over MgSO4 and concentrated. The resulting product is purified by preparative HPLC, affording Compound (35) as white-off solid (10.5 mg; 6%). 1H NMR (DMSO-d6, 300 MHz) δ 2.12 (s, 3H), 2.45 (s, 3H), 4.75 (s, 2H), 7.61 (s, 1H), 12.08 (s, 1H). M− (ESI): 268.11; M+ (ESI): 270.16. HPLC (method A), Rt: 1.74 min (purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[O:7])=[CH:4][CH:3]=1.O.C(OCC)C.[BrH:24]>>[Br:24][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Br
Reactant: O=C(NCCCCCCO)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O
Product: O=C(NCCCCCCBr)c1ccc(Cl)cc1

Procedure:
6-(4-Chlorobenzoylamino)hexan-1-ol (17.0 g) was refluxed in 48% hydrobromic acid (260 ml) for 2.5 h. The mixture was cooled and added to water (450 ml) and diethyl ether (450 ml). The organic layer was washed with saturated sodium bicarbonate (450 ml) and brine (450 ml) and was dried over magnesium sulfate. Evaporation followed by recrystallisation from diethyl ether gave 1-bromo-6-(4-chlorobenzoylamino)hexane (8.6 g). 1H-NMR (CDCl3) δ 1.3-2.0 (8H, m), 3.35-3.55 (4H, m), 6.15 (1H, bs), 7.40 (2H, m) and 7.70 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8]2=[O:15].[OH-].[NH4+:21]>>[NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:8]([NH2:21])=[O:15])[C:11](=[CH:12][CH:13]=1)[C:10]([NH2:9])=[O:14]
Reactant: Nc1ccccc1Oc1ccc2c(c1)C(=O)NC2=O
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(Oc2ccccc2N)cc1C(N)=O

Procedure:
5-(2-Aminophenoxy)-isoindole-1,3-dione (0.1 g, 0.38 mmol) in conc. ammonium hydroxide (aq) was stirred at 60° C. for two hours. The reaction mixture was evaporated in vacuo (cold in order not to make the imide again). The crude mixture was used without any purification.
Reaction SMILES: C([O:5][P:6]([O:38]C(C)(C)C)([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])=[O:7])(C)(C)C.P(OC(C)COC(N1C2C(=CC=C(C(F)(F)F)C=2)[C@@](C2C=C(Cl)C=CC=2OC)(F)C1=O)=O)(O)(O)=O>>[P:6]([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])([OH:7])([OH:38])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Agent: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCCOP(=O)(O)O)c2cc(C(F)(F)F)ccc21

Procedure:
Using (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-ethyl ester ((S)-VII, n=1) as starting material, the title compound was prepared analogously to (S)-3-(5-Chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxy-propyl ester; (S)-Ib, n=2) in 83%. 1H NMR (CDCl3, 500 MHz) δ 8.23 (s, 1H), 7.73 (d, 1H), 7.45 (d, 1H), 7.30 (d, 1H), 7.28 (d, 1H), 6.75 (d, 1H), 4.59 (m, 2H), 4.33 (m, 2H), 3.51 (s, 3H); MS (m/e) 525.95 (M+−1); 31P NMR (CDCl3, 500 MHz) δ 1.87; 19F NMR (CDCl3, 500 MHz) δ−63.25, 153.8; Anal. Calcd. for C19H15ClF4NO8P·0.159H2O: C=41.60%, H=3.18%, N=2.55%; Found: C=41.57%, H=2.92%, N=2.51%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[CH:13]([NH:15][NH2:16])=O.C1(O)CCCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:13]=[N:15][N:16]=[C:7]1[CH2:6][CH2:5]2
Reactant: NNC=O
Reactant: S=C1CCc2cc(Br)ccc2N1
Solvent: OC1CCCCC1
Solvent: O
Product: Brc1ccc2c(c1)CCc1nncn1-2
Temperature: 120 °C

Procedure:
A flask containing the title compound from Example 22, Step A (0.200 g, 0.826 mmol), formic hydrazide (0.099 g, 1.65 mmol) and cyclohexanol (6.00 ml, 0.826 mmol) was heated to 120° C. for 16 hours. The reaction was then cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 251.90 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 7.63-7.54 (m, 3H), 3.19-3.16 (m, 2H), 3.11-3.08 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]([NH:1][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1)[C:7]([O:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H](NCc1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of cyclopentyl L-leucinate (2.00 g, 10.0 mmol) and 4-nitrobenzaldehyde (3.04 g, 20.0 mmol) in DCM (40 ml) was added glacial acetic acid (2 drops). The solution was allowed to stir at RT for 1 h whereupon sodium triacetoxyborohydride (6.40 g, 30.2 mmol) was added in a single a portion. After stirring for 3 h, the solution was poured on to aq. 1M HCl, allowed to stir for 30 min, neutralised with aq. 1M NaOH and extracted with DCM. The combined organics were washed with water and brine, dried over MgSO4, and evaporated under reduced pressure. The crude material was purified by chromatography (5% EtOAc/isohexane) to furnish the title compound as an oil (1.51 g, 45%). m/z 335.1 [M−H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[N:9][C:8](Cl)=[C:7]2[NH:12][N:13]=[CH:14][C:6]=12.[Cl-].[NH4+]>>[Br:4][C:5]1[CH:10]=[N:9][C:8]([O:2][CH3:1])=[C:7]2[NH:12][N:13]=[CH:14][C:6]=12
Reactant: Clc1ncc(Br)c2cn[nH]c12
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1ncc(Br)c2cn[nH]c12
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Sodium methoxide (28% in MeOH) (3 ml) was added to 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (126 mg) obtained in the 2nd step, followed by stirring at 90° C. for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution and an insoluble precipitate was collected by filtration. The obtained residue was washed with water and a yellow solid of 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine (133 mg) was thus obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.CCOCC>[CH3:20][O:19][C:17]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
A mixture of (S)-2-amino-3-methylbutanoic acid (10.0 g, 85.0 mmol), NaOH (3.41 g, 85.0 mmol) and NaHCO3 (4.7 g, 44.4 mmol) in H2O (85 mL) was cooled to 0° C. A mixture of methyl chloroformate (7.3 mL, 94.0 mmol) dissolved in Et2O (40 mL) was slowly added to the aqueous mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pH 2.0 with HCl (conc). The mixture was extracted with CH2Cl2 (3×100 mL) and then dried (MgSO4), filtered and concentrated to afford 7.5 g (50%) of the title compound. MS (ESI) m/z 176 (M+H)+.