Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4])=[O:16])[CH:19]=[CH2:20]
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO)COCc1ccccc1
Yield: 94.2 %

Procedure:
A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ 2.56 (br s, 1 H), 3.69 (m, 3 H), 3 88 (m, 2 H), 4.54 (s, 2 H), 4.58 (d, 2 H, J=5.6 Hz), 5.23 (dd, 1 H, J=10.4, 1.1 Hz), 5.33 (dd, 1 H, J=17.1, 1.1 Hz), 5.42 (m, 1 H), 5.93 (m, 1 H), 7.35 (m, 5 H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[H][H]>[Pd]>[F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][CH2:7][CH3:8])=[O:4]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Product: CCCNC(=O)C(F)(F)F

Procedure:
In Reaction Scheme 4, 6-amino-4-methoxypyrazolo[3,4-d]pyrimidine was converted to the iodo derivative (14) which was treated with 1-chloro-1,2-dideoxy-3,5-di-O-toluoylribofuranose to yield the nucleoside (15). Compound (15) was treated with NaOMe/MeOH to hydrolyze the toluoyl groups and yield the unblocked nucleoside (16). Treatment of (16) with aqueous sodium hydroxide gave (17) which could be converted to the trifluoro-N-prop-2-ynyl acetamide derivative (18). Compound (18) was reduced with hydrogen and a Pd catalyst to yield the trifluoro-N-propylacetamide derivative (19). The 4-amino group of compound (19) was protected by treatment with N,N-dimethylformamide dimethylacetal to give compound (20) which was converted to DMTr derivative (21) and then to the phosphoramidite derivative (22).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)(Cl)(=[O:18])=[O:17]>ClCCl>[S:16]1(=[O:18])(=[O:17])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][O:8]1
Reactant: OCC1CCCCN1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1(=O)OCC2CCCCN21
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a −78° C. hazy solution under a nitrogen atmosphere of racemic 2-piperidinemethanol (0.576 g, 5.00 mmol) and triethylamine (1.42 mL, 10.0 mmol) in anhydrous dichloromethane (30 mL) was added a solution of sulfuryl chloride (0.41 mL, 5.06 mmol) in anhydrous dichloromethane (30 mL) and the reaction was stirred for around 18 h from −78° C. to ambient temperature. The clear, yellow solution was washed with 1.0N HCl (2×25 mL) and brine (25 mL), dried over Na2SO4, concentrated in vacuo to a dark yellow oil, and purified by flash column chromatography (silica gel, ether) to afford the title product as a clear yellow oil (0.342 g, 39%). The proton NMR was identical to the desired product in procedure A, step 2.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1.BrC1C=CC2[NH:31]C(C(Cl)(Cl)Cl)=NC=2C=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:6]([C:7]([NH2:31])=[O:9])=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Reactant: ClC(Cl)(Cl)c1nc2cc(Br)ccc2[nH]1
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(N)=O)c(N)n3)nc1-2

Procedure:
A solution of benzimidazole-2-aldehyde 1 (0.5 mmol) and diamine 2 (0.5 mmol) in dimethylacetamide (4 mL) was stirred at 100° C. for 12 h. Solvent was evaporated and residue was purified by preparative HPLC to give benzimidazole derivative 3. 1H NMR (300 MHz, MeOH-d4): δ 2.52 (s, 3H), 2.85 (brs, 4H), 3.25 (brs, 4H), 7.05-7.15 (m, 2H), 7.25-7.35 (s overlapped with m, 2H), 7.60-7.75 (m, 4H); LCMS m/z 333 (M+H+), ELSD 99%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2>CS(C)=O.O>[N:1]1([C:8]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c2cccnc12
Temperature: 100 °C
Yield: 80.4 %

Procedure:
Morpholine (251.6 μl, 2.88 mmol) was added to a solution of 5-chloro-8-nitro-quinoline 27 (200 mg, 0.96 mmol) in DMSO (2 ml) and the mixture was heated at 100° C. in a sealed tube for 18 h. After cooling, the mixture was diluted with water (10 ml) and the resulting precipitate was collected by filtration. The solid was dried in vacuo to give the title compound (200 mg, 81%) which was used in the next step without further purification.
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].[NH4+].[Cl-]>C1COCC1>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: ClCCCCBr
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) was added drop wise to a solution of iPr2NH (12.3 mL, 88 mmol, distilled from NaOH) in dry THF (150 mL) in 10 min. The reaction mixture was stirred for 20 min, cooled to −70° C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem., 1937, 43, 282-285, 12.5 g, 88 mmol) was added drop wise in 20 min. After 3 min, 1-bromo-4-chlorobutane (13.7 mL, 20.1 g, 117 mmol) was added drop wise in 15 min. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (1×200 mL, 1×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The remaining oil, was purified by fractional distillation to give tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.73 g, 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR (CDCl3): δ=3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Br:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([Br:20])=[CH:22][CH:23]=2)[CH2:30][CH2:31]1)=[O:19])[CH3:2]
Reactant: C#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Br)cc1
Product: C#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (21.62 g, 76.7 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (31.9 g, 92 mmol), 23 g of the ester derivative was isolated. Yield: (58%); yellow oil; MS: 521.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-])=O.Cl>CO.O1CCOCC1.[Pt]>[ClH:18].[NH2:1][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(Cl)c(C)nc12
Agent: [Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(N)c1CNc1cccn2c(Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.1 %

Procedure:
A solution of 8-(2-nitro-6-methylbenzylamino)-3-chloro-2-methylimidazo[1,2-a]pyridine (2.0 g, 6 mmol) in methanol (175 ml) and dioxane (175 ml) is treated with platinum-on-carbon catalyst (5% strength) and hydrogenated at RT under atmospheric pressure for 2 h. After 2 h, 2N hydrochloric acid (5 ml) is added and the mixture is hydrogenated under the same conditions again for 1 h. The catalyst is then filtered off, the filtrate is adjusted to pH 8.5 using 2N sodium hydroxide solution and the solvent is distilled off on a rotary evaporator. The residue is dissolved in boiling ethyl acetate (400 ml). After cooling to RT, diisopropyl ether (250 ml) is added and, to complete crystallization, the mixture is stirred at 4° C. for 30 min. The precipitate is then filtered off with suction, washed with diisopropyl ether and dried in vacuo. The title compound (1.66 g, 92%) is isolated as a beige solid. M.p. 243-246° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(=[O:28])C.[Li+]>C(O)(C(F)(F)F)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3](/[C:19](/[OH:28])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C#Cc1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Agent: [Pd+2]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C(\O)c1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of ethyl 4-(3-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (0.5 g, 1 mmol) in 1.5 mL TFA was stirred at room temperature and treated with lithium acetate (0.09 g, 1 mmol) and palladium(II) acetate (0.02 g, 0.07 mmol). The resulting solution was stirred at room temperature for 2 hours and concentrated. The residue was diluted with 100 mL EtOAc, washed with water (3×20 mL), 20 mL saturated NaCl, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 0.15 g of the product as a yellow oil. MS m/e: (M+H)+ 383.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:20][C:21]([O:23]CC)=O)[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:26]([N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][NH:34][C:21](=[O:23])[CH2:20][N:12]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[N:11]1)[CH3:27]
Reactant: CCOC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1

Procedure:
A solution of 7.5 g (0.022 mol) of ethyl 4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate of example 5 in 35 mL of diethylaminopropylamine was stirred on a steam bath under nitrogen for 14 hours. The diethylaminopropylamine was removed in vacuo and the residue taken up in 200 mL of ethyl acetate. The ethyl acetate solution was washed twice with water, once with brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was distilled in a Kugelrohr at 250° C./0.1 mm to yield 6.39 g of N-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide as a clear viscous amber oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:36][CH2:35][CH2:34][CH:33]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:35]4[O:36][CH2:32][CH2:33][CH:34]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C1=C(c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)OCC1
Yield: 72.2 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 5-(tributylstannyl)-2,3-dihydrofuran (250 mg, 0.70 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (10 ml) and heated at reflux under nitrogen for 2 hr (Procedure B). The solvent was removed from the cooled reaction under vacuum, and the residue was suspended in 1:1 iso-hexane/ethyl acetate and filtered. The solvent was removed from the filtrate under vacuum to give the product (140 mg, 72%) as a yellow solid; δH [2H6]-DMSO 9.88 (1H, b, NH), 8.62 (1H, s, 5-H), 8.50 (1H, s, 2-H), 8.05 (1H, d, 7-H), 7.67 (3H, m, 8-H, 2′-H, 6′-H), 7.55-7.29 (5H, m, 5×Ph-H), 7.03 (2H, m, 3′-H, 5′-H), 5.81 (1H, s, 3″-H), 5.12 (2H, s, PhCH2), 4.52 (2H, t, 5″-H2), 2.88 (2H, t, 4″-H2); m/z 396 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C:26](C)([CH3:29])[CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@@H:26]([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaminolinstead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24]#[N:25])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:33][OH:34]>C(O)C>[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24](=[N:33][OH:34])[NH2:25])=[O:15])=[CH:12][CH:13]=1
Reactant: CON=C1C[C@@H](C#N)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 81.8 %

Procedure:
According to the general method outlined above for the synthesis of Intermediates 8, triethylamine (1.94 ml, 13.94 mmol) was slowly added to a suspension of (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbonitrile (3.71 g, 11.62 mmol) and hydroxylamine.hydrochloride (0.97 g, 13.94 mmol) in ethanol (150 ml), under stirring. The reaction mixture was allowed to stir at 80° C. for 16 h, and then cooled to ambient temperatures. The solvent was removed by evaporation and the solid was suspended in water (100 ml) then filtered. The solid was washed with diethyl ether (2×100 ml) whilst on the sinter and then dried in vacuo at 40° C., to give the desired product, (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (3.35 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([O:24]C)=O)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([NH2:32])=[O:24])=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 38, 92.1 mg of methyl 3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 15 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][N:21]3[Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[C:13]([C:36]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:12]=1)C1C=CC=CC=1>[OH-].[K+].CO.O.O>[NH2:10][C:11]1[CH:12]=[C:13]([C:36]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:14]=[C:15]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[CH:16]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(NC(=O)OCc4ccccc4)cc(C(=O)c4cccnc4)c3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
[3-(Pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid benzyl ester (40 mg, 0.066 mmol) in 40% KOH in MeOH/H2O (5 mL/5 mL) was brought to reflux for 2 hours. After cooling down to room temperature, the mixture was diluted with water, and extracted with EtOAc. The organic layers were separated, dried and concentrated. Purification on silica gel afforded [3-amino-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone as a yellow solid (11.9 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 9.01 (d, J=1.6 Hz, 1H), 8.71 (dd, J=4.8, 1.7 Hz, 1H), 8.29 (s, 1H), 8.09 (dt, J=4.9, 2.6 Hz, 1H), 7.38-7.31 (m, 3H), 7.20-7.15 (m, 4H), 7.11-7.07 (m, 2H) 6.64-6.60 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1C#N.OS(O)(=O)=O.[C:18](=[O:21])([O-])[O-:19].[Na+].[Na+]>O>[Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:18]([OH:19])=[O:21]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
2-Bromo-4-nitro-benzonitrile (0.5 g, 2.34 mmol) was hydrolysed using H2SO4 (2.2 mL) in water (2.7 mL) at 80° C. for 8 h. After completion of reaction, the solution was poured over crushed ice, basified with sodium carbonate and extracted with EtOAc. Aqueous layer was separated, acidified with 1:1 HCl and extracted with EtOAc (3×100 mL). The combined organic layers were concentrated to obtained compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(C(F)(F)F)cc2)sc1C(=O)NCc1ccccc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 45% yield; 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.2 Hz, 2H), 7.36-7.29 (m, 5H), 5.97 (s, 1H), 4.60 (d, J=5.6 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:31][CH:30]([CH2:32]Br)[CH2:29][C:28]=2[CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([OH:13])[CH2:8][CH2:9][N:10]([CH2:32][CH:30]3[CH2:29][C:28]4[CH:34]=[C:24]([O:23][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:25]=[CH:26][C:27]=4[O:31]3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: OC1(Cc2ccc(F)cc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 74.1 %

Procedure:
Using the procedure from Example 14A, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 3,4-dichlorobenzenesulfonyl chloride (191 mg, 0.12 mL, 0.78 mmol) to afford the title compound (211 mg), a white solid, in 74% yield.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 34 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and methanesulfonyl chloride as starting material, 20 mg (34%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.49 (s, 1H), 8.39 (d, 1H), 8.32 (s, 1H), 7.92 (d, 1H), 7.84-7.78 (m, 5H), 7.04 (s, 1H), 4.91 (s, 2H), 4.38-4.33 (m, 2H), 3.84-3.78 (m, 1H), 3.38-3.30 (m, 2H), 3.23 (s, 3H), 2.74-2.69 (m, 2H), 2.38-2.30 (m, 2H); LC-MS m/z [M+H]+ 519.2, RT 3.13 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[OH:20])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: Br[Mg]C1CCCCC1
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SCCC(O)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
By the method of Example 14, the aldehyde of Example 4 was reacted with 7.1 ml of 1.97M cyclohexyl magnesium bromide in tetrahydrofuran to give the title alcohol. Analysis calc. for C23H38O2S(378.60):