Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-cyanocyclohexanecarboxylate (996 mg, 5.96 mmol) in THF (37 mL) was added a solution of 0.5 M lithium hydroxide in water (20 mL). The mixture was stirred overnight then the THF was removed in vacuo and the residual aqueous solution acidified to pH 4. The resulting mixture was extracted with ether (2×30 mL), EtOAc (2×30 mL) and CHCl3 (2×30 mL) then the combined extracts, dried over anhydrous sodium sulfate and concentrated in vacua. This material was taken to the next step without any purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.73 (4 H, m), 2.05-2.22 (4 H, m) and 2.36-2.59 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 332) (0.100 g, 0.28 mmol) in DMF (2.8 mL) was added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution was stirred with heating to 60° C. overnight. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate and 10% citric acid. After extracting with ethyl acetate, the combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography (SiO2, 1:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.096 g, 76%). mp 110-113° C. 1H NMR (300 MHz, DMSO d6) δ 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59-7.71 (m, 3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 467 (M+H)+, 484 (M+NH4)+. Anal. calc. for C24H19ClN2O4S: C, 61.73; H, 4.10; N, 6.00. Found: C, 62.00; H, 4.18; N, 5.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([OH:32])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][O:59][C:60]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:61]=1[CH2:62][NH2:63].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([NH:63][CH2:62][C:61]3[CH:64]=[CH:65][C:66]([O:68][CH3:69])=[CH:67][C:60]=3[O:59][CH3:58])=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)NCc2ccc(OC)cc2OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.1 h

Procedure:
To a solution of 43 mg (0.09 mmol) of 3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid (Example 81, Step B) in DMF (5 mL) was added 67 mg (0.18 mmol) of HATU, 58.5 mg (0.35 mmol) of 2,4-dimethoxybenzylamine and 36 μL (0.26 mmol) of triethylamine. The resulting yellow solution was stirred at room temperature for 1.1 h, and then was partitioned between saturated aqueous sodium bicarbonate and EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of alcohol epimers) was used directly in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[C:27]([NH2:28])=[CH:26][NH:25][N:24]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]=[C:15]1[C:23]1[C:27]([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:26][NH:25][N:24]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)c1cccc2cccnc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1cccc2cccnc12
Yield: 6.2 %

Procedure:
A mixture of quinoline-8-carboxylic acid (104 mg, 0.60 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) was stirred at room temperature in DMF (1.5 ml) for 20 h. The reaction mixture was purified by preparative LC/MS to give quinoline-8-carboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide (11 mg, 6%) as a brown solid. (LC/MS: Rt 3.85, [M+H]+ 355.11).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH:22]=[C:21]([C:30]([OH:32])=O)[CH:20]=2)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:50][C@H:51]([NH2:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:50][C@@H:51]([NH:59][C:30]([C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=1)=[O:32])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3nccs3)c2)cc1
Reactant: C[C@H](N)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3nccs3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to a solution of 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (63 mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.0 mmol) in CH2Cl2 (3 mL). After the reaction stirred at 0° C. for 1 hour, (S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to afford (R)-4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (72 mg, 81%). MS (M+H)=422.
Reaction SMILES: [CH:1]1([C:7](=[O:22])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[O:32]>C1COCC1>[CH2:35]([O:34][C:30](=[O:33])[CH:31]([OH:32])[CH:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:13][CH:14]=1)[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:22])[CH3:36]
Reactant: CCOC(=O)C=O
Reactant: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)C(C(=O)C1CCCCC1)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
To a stirred solution of 1-cyclohexyl-2-(4-cyclohexyloxy-phenyl)-ethanone (1.17 mmol, 0.35 g) and triethylamine (1.17 mmol, 0.16 mL) in THF (1.0 mL) was added a solution of ethyl glyoxylate (50% in toluene, 5.83 mmol, 1.15 mL) and continued stirring for 12 h at room temperature. After removal of volatiles under reduced pressure, the crude product was purified on a 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 4-cyclohexyl-3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-butyric acid ethyl ester (0.28 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCc2ccccc2)[nH]n1
Yield: 54.5 %

Procedure:
Hydrazine hydrate (0.109 mL, 2.24 mmol) was added to a stirring room temperature solution of 19 (0.5570 g, 2.24 mmol) in EtOH (2.2 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH). Only pure fractions were combined and concentrated to obtain 0.2983 g (54.4%) of 20. 1H (CDCl3, 400 MHz): δ 11.7 (1H, broad s), 7.30-7.11 (5H, m), 6.60 (1H, s), 4.32 (2H, q, J=7.1 Hz), 3.07-2.92 (4H, m), 1.31 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.13, 147.42, 140.97, 128.72, 128.59, 126.48, 106.79, 61.16, 35.63, 28.18, 14.47 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 61.16, 35.63, 28.18; CH carbons: 128.72, 128.59, 126.48, 106.79 ppm. HPLC: 9.299 min.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][NH2:34].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCN
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 59.8 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and 1,3-diaminopropane (3.3 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-aminopropylamino)-cholestan-3β-ol as a white solid (6.3 g, 60%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH2:26](I)[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:26][CH3:27])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: CCI
Product: CCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c(C#N)c1=O
Yield: 76.8 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 76.8%.
Reaction SMILES: O[C@@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:38]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C(C)=CC=CC=1C.II.[Cl-]>C(Cl)(Cl)(Cl)Cl>[I:38][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1
Reactant: II
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CC[C@H]1C
Agent: [Cl-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@@H]1C[C@H](I)CC[C@H]1C

Procedure:
reacting said ethyl (1R,2R,5S)-5-hydroxy-2-methylcyclohexane-1-carboxylate (12) with Ph3P-imidazole-I2 (or Ph3P-2,6-lutidine-I2) in a carbon tetrachloride/methlylene chloride mixture to produce ethyl (1R,2R,5R)-5-iodo-2-methylcyclohexane-1-carboxylate (4a).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:21][N:20]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Yield: 79.7 %

Procedure:
Prepared as in Example 104 from (2,3-difluorophenyl)-(4-methoxy-phenyl)-methanone (1.1 g, 4.4 mmol), hydrazine hydrate (1.37 mL, 44 mmol) and DMAP (0.54 g, 4.4 mmol) to give the product (0.85 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([CH2:9][OH:10])[O:3]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[C:15]1([CH2:14][O:8][CH2:7][C@@H:5]2[C@@H:4]([CH2:9][O:10][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:3][C:2]([CH3:11])([CH3:1])[O:6]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@H](COCc2ccccc2)[C@@H](COCc2ccccc2)O1
Reaction time: 0.75 h
Yield: 120.7 %

Procedure:
A solution of (4R-trans)-(-)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (51 g) in THF (400 ml) was added dropwise to a stirred suspension of sodium hydride (17.5 g of 80% in oil) in THF (200 ml). After 0.75 h, benzyl bromide (116.3 g) was added dropwise and the resulting mixture was stirred for 18 h, and was then heated at reflux for 2 h. After stirring for a further 20 h at 20°, the mixture was cooled in ice, water (10 ml) was added and the mixture was evaporated to dryness. The residue was extracted with ER, and the organic solution was dried and the solvent was evaporated giving a crude product (130 g) which was used without further purification.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17])=[O:4]
Reactant: O=C(O)CC1C=CC=CC1=NO
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=C(O)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of methylene chloride (45 ml) and dichloroacetyl chloride (10 ml) was added portionwise with stirring 2-hydroxyiminophenylacetic acid (synisomer) (5g) in portions over about fifteen minutes. The reaction mixture became solid, and was stirred for one hour at room temperature after the addition was complete. The reactior was diluted with petroleum (b.p. 40°-60° ), filtered, and the solid washed several times with petroleum spirit to remove residual acid chloride. The solid was dried under vacuum, giving 2-dichloroacetoxyiminophenylacetic acid (syn-isomer)(8.0g; 96%), m.p. 115°, λmax. (CHBr3) 3470 and 1750 (-CO2H), 1765 cm. -1 (ester), τ (CDCl3) values include 2.0 - 2.7 (multiplet; aromatic protons), 3.85 (singlet; -CHCl2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:11]([OH:14])(=[O:13])=O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:11]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:13])=[O:14])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(S(=O)(=O)O)c1
Reactant: CC(C)(C)N
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 3-bromo-5-nitrobenzenesulfonic acid (1.86 g, 6.59 mmol) in toluene (37 mL) and phosphorus pentachloride (2.75 g, 13.2 mmol) were heated at 100° C. overnight. The reaction mixture was cooled to 0° C. and treated with tert-butylamine (1.03 mL, 9.89 mmol) and N,N-diisopropylethylamine (5.74 mL, 33.0 mmol). After stirring at 25° C. for 30 min, the reaction mixture was diluted with 1 N HCl and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.2 g, 98%). 1H NMR (400 MHz, (400 MHz, DMSO-d6): δ 8.62 (m, 1H), 8.56 (m, 1H), 8.37 (m, 1H), 8.03 (s, 1H), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:5](\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: ClCC/C(=C(\c1ccccc1)c1ccc(OCCN2CCCC2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: ClCCC(c1ccccc1)C(c1ccccc1)c1ccc(OCCN2CCCC2)cc1

Procedure:
(RR, SS)-isomers: A mixture containing 43.2 g of (Z)-4-chloro-1,2-diphenyl-1-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-butene, 4 g of 5% palladium-on-charcoal and 800 ml of glacial acetic acid is stirred under hydrogen atmosphere at 75° C. until one equivalent of hydrogen is consumed, about 6 h. The solvent is evaporated and the evaporation residue is dissolved in toluene. The toluene solution is washed first with 2 M sodium hydroxide solution and then with water, after which the solution is dried over sodium sulfate. Finally the solvent is evaporated leaving the product as an oil at quantitative yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11]I>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Oc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cccc(Br)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-bromo-pyridin-2-ol (10 g, 57.47 mmol) in DMF (100 ml) at 0° C. was added NaH (60%, 2.52 g, 63.22 mmol) portionwise under argon. After 30 min methyl iodide (4.29 ml, 68.97 mmol) was added dropwise and the reaction mixture was stirred for 15 h at RT. The mixture was diluted with ethyl acetate (100 ml), washed with water (2×200 ml) and brine (100 ml), dried over Na2SO4, and evaporated under reduced pressure. The crude product was used without further purification in step 21.5).
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=1)[CH2:21][CH3:22].[C:40]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCCl>[CH2:29]([N:28]1[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=[C:23]1[CH:20]([NH:19][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:21][CH3:22])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCCCC1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Acetic acid (65 μl, 0.95 mmol) and sodium triacetoxyborohydride (200 mg, 0.95 mmol) were added to a solution of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 180 mg, 0.64 mmol) and cyclohexanone (62 mg, 0.64 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred for 4 h at room temperature concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound (211 mg, 91%) as a white solid: 1H NMR (DMSO-d6) δ 0.69–1.19 (m, 10H), 1.38–1.89 (m, 6H), 1.99 (m, 1H), 3.63 (m, 1H), 4.82 (m, 1H), 5.80 (m, 1H), 6.55 (s, 1H), 7.06 (s, 1), 7.15 (m, 2H), 7.22–7.35 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1.N1C=CC=CC=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:1]1[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc[nH][nH]1
Solvent: c1ccncc1
Product: CC(=O)n1ccc(=O)[nH]1
Temperature: 95 °C

Procedure:
A mixture of 1,2-dihydro-3H-pyrazol-3-one (4.50 g, 26.8 mmol), in pyridine (20.4 mL, 252 mmol) was heated to 95° C. then charged with a solution of acetic anhydride (5.10 mL, 54.0 mmol) in pyridine (9.64 mL, 119 mmol) over a 15 min period. The reaction was heated for an additional 1 h at 95° C. The reaction mixture was concentrated in vacuo resulting in a dark red oil which was triturated with MeOH and filtered resulting in the title compound as a light yellow solid. A 2nd crop of product was isolated from the mother liquors. 1H NMR (400 MHz, DMSO-d6): δ=2.48 (s, 3H) 6.00 (d, J=3.0 Hz, 1H), 8.12 (d, J=3.0 Hz, 1H), 10.95 (br. s., 1H). MS (ES+): m/z 127.23 (100) [MH+]. HPLC: tR=0.82 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1I.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(C(F)(F)F)c(F)cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(F)c(C(F)(F)F)cc2F)OC1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 101.4 %

Procedure:
1,4-difluoro-2-iodo-5-(trifluoromethyl)benzene (500 mg, 1.6 mmol) was dissolved in dry THF (7 mL), cooled to 0° C. and treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.4 mL, 1.3 M, 1.8 mmol) and stirred for 40 min at 5° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 μl, 330 mg, 1.8 mmol) was added and stirring was continued for 1 h. After treating with sat. NH4Cl, the mixture was shaken with ethyl acetate. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to give the title compound as a light brown oil (500 mg, 100%). The material was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J=9.9, 4.3 Hz, 1H), 727 (dd, J=8.0, 5.2 Hz, 2H), 1.37 (s, 12H). 19F NMR (376 MHz, CDCl3) δ −62.10, −62.13, −106.85, −106.90, −121.81, −121.87, −121.90.