Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:31][C:32]#[N:33])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:31]([CH2:1][CH3:2])[C:32]#[N:33])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.3 %

Procedure:
Potassium t-butoxide (908 mg, 8.09 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (1.41 g, 3.68 mmol) and ethyl iodide (1.43 g, 9.20 mmol) in tetrahydrofuran (18 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.20 g, 2.92 mmol, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8](O)[N:7]=[CH:6][N:5]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([Cl:14])[N:7]=[CH:6][N:5]=1
Reactant: COCc1ncnc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COCc1ncnc(Cl)c1C
Temperature: 0 °C

Procedure:
4-Methoxymethyl-5-methyl-6-hydroxypyrimidine (38.40 g) was stirred with phosphorus oxychloride (275 ml) at room temperature for 24 hours. The mixture was stripped, ice/water added and the pH raised to 11.5 (NaOH). The solution was extracted with chloroform, extracts dried (MgSO4) and stripped to give 4-methoxymethyl-5-methyl-6-chloropyrimidine, 38.23 g, as an oil, which solidified on cooling to 5° (m.p. 37°-38°). It was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])#[C-:11]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C@@H:6]2[O:7][CH:11]=[N:10][C@H:12]2[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: [C-]#[N+]CC(=O)N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
SLA 09052B was prepared in accordance with method D using thiophene-3-carbaldehyde (0.778 mL, 5.43 mmol), KOH (0.273 mg, 4.94 mmol) in methanol (5 mL) and 2-isocyano-1-(piperidin-1-yl)ethanone SLA 07116B (0.75 g, 4.94 mmol). The solution was stirred for 2 h at 0° C. After work-up (without any further purification) and drying trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(piperidin-1-yl)methanone SLA 09052B was obtained as a yellow oil (1.29 g, 99% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:5](=[O:6])[C:4]4[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:3]=4[C:2]([F:17])([F:16])[F:1])[CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,5-bis-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (50% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 7.99, 7.92-7.9, 7.85-7.84, 7.65, 7.02, 4.13-4.08, 3.95-3.71, 3.57-3.55, 3.38-3.36, 1.57-1.44, 0.8-0.7, 0.48-0.46, 0.16-0.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCSCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 5.83 mmol) and acetaldehyde (513 mg, 11.66 mmol) in dichloroethane (50 mL), acetic acid (2.0 ml, 34.9 mmol) was added and reaction was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.7 g, 17.49 mmol) was added and stirred at room temperature for overnight. The mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. The crude material was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzoate (2.0 g, 74.0%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:32]([C:34]1[CH:39]=[C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:37]=[CH:36][CH:35]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(C#N)c3)c2c1
Yield: 3.4 %

Procedure:
N-[3-(3-Cyanophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.75 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 380 mg of 3-cyanophenylboronic acid, 30 ml of dimethylformamide, 2.85 ml of a saturated aqueous sodium hydrogencarbonate solution and 37 mg of tetrakis(triphenylphosphine)palladium[0]. 20 mg of N-[3-(3-cyanophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 240° C. (analysis C21H16N4O4S2.H2O % calculated C, 53.61; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.95; H, 3.85: N, 11.68; S, 13.18).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([C:11]2[CH:19]=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:1]([C:19]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)=[O:3]
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccccc2)nn2ccccc12
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
A solution of sodium nitrite (533 mg) in water (2.5 ml) was added dropwise to a solution of 2-phenylpyrazolo[1,5-a]pyridine (1.0 g) in acetic acid (5 ml) at 13° to 15° C. After being stirred at the same temperature for 20 minutes, the reaction mixture was poured onto ice-water. Resultant precipitates were collected by filtration, washed with water and recrystallized from acetone to give crystals of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.82 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Product: COc1cccc(-c2ccc(C(OC)C(=O)NCc3ccc(C#N)cc3)c(F)c2)c1

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with 3-methoxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-3′-methoxy-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1
Reactant: OC1C=CC(O)(CCCCOc2ccccc2)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1C=CC(O)(CCCCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
1.9 g (7.6 mmoles) of 3,5-dihydroxy-3-(4-phenoxybutyl)cyclopentene was dissolved in 15 ml of dichloromethane, and at 0° C. 5.7 g (15 mmoles) of pyridinium dichromate was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 200 ml of ether, and filtered through Celite. After concentration, 1.32 g (71%) of 4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone was obtained.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[CH3:20][N:21]([CH3:29])[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCOCC1>[CH2:27]([O:26][C:24](=[O:25])[C:23](=[CH:22][N:21]([CH3:29])[CH3:20])[C:11](=[O:12])[C:10]1[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:9]=1[F:8])[CH3:28]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.09 mL, 15 mmol) was added with stirring to a solution of 2,4,5-trifluorobenzoyl chloride (1.95 g, 10 mmol) and ethyl 3-dimethylaminoacrylate 20 (1.43 g, 10 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at r.t. overnight, and solvent was removed under vacuum. The residue was dissolved in ethyl ether (100 mL) and hexanes (20 mL), and the resulting mixture was washed with water (2×100 mL), 2% aq. citric acid (2×100 mL), brine (100 mL), 2.5% aq. NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried (MgSO4), and the solvents removed under vacuum to provide ethyl-2-(dimethylamino)methylene-2-(2,4,5-trifluorobenzoyl)acetate 21 as a light orange oil (Yield 2.55 g (85%). MS (m/z): 302 [M+H]+. Rt 4.9 min.). A solution of Compound 21 (0.301 g, 1.0 mmol) and 5-(S)-acetamidomethyl-3-(4-amino-3-fluorophenyl)-oxazolidine-2-one (0.267 g, 1.0 mmol) in EtOH (9 mL) was agitated at 40° C. for 16 h. The solvent was removed under vacuum, and the resulting residue dissolved in ethyl ether (75 mL). The ether solution was washed with 3% aq. citric acid (2×40 mL), brine (40 mL), and dried (MgSO4). The solvent was removed under vacuum to afford Compound 22 as a thick light-orange oil. Yield 0.50 g (90%). MS (m/z): 524 [M+H]+. Rt 5.5 min.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH:12]([CH3:14])[CH3:13]
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure B′ above, and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 62° C.-64° C. The reaction was monitored by tlc on silica gel (Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[C:12]([S:16]([NH2:19])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(S(N)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of Benzenesulfonamide-3-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA41 (9.2 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.0.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([NH:6][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:8]=3)[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:11]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NCC3CC3)ccc2n1Cc1cccc(OC)c1
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Cyclopropanecarboxaldehyde (168 mg, 2.4 mmol) was added to a stirred mixture of ethyl 5-amino-3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 160, 530 mg, 1.2 mmol) in toluene (12 mL) and molecular sieves (2 g). The reaction was stirred for 16 h and then filtered using toluene to rinse. The filtrate was concentrated in vacuo and the residue was dissolved in methanol (12 mL). Sodium borohydride (15 mg, 1.2 mmol) was added and the reaction was stirred for 2 h. The mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate afforded 480 mg (78%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.45-7.48 (m, 2 H), 7.34-7.38 (m, 2 H), 7.31 (d, 1 H), 7.18 (dd, 1 H), 6.87 (dd, 1H), 6.77 (ddd, 1 H), 6.65-6.70 (m, 2 H), 6.62 (d, 1 H), 5.75 (s, 2 H), 4.68 (s, 1 H), 4.08 (q, 2 H), 3.69 (s, 3 H), 2.89 (d, 2 H), 1.37 (s, 9 H), 1.00-1.10 (m, 1 H), 0.93 (t, 3 H), 0.42-0.49 (m, 2 H), 0.16-0.25 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 100 °C

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.14 g, 0.70 mmol), acetonitrile (4 mL), potassium carbonate (0.09 g, 1.75 mmol) and iodoethane (0.12 g, 0.77 mmol) was heated under microwave irradiation at 100° C. for 5 minutes. Water (30 mL) was added and the aqueous phase extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:1 to 1:1) gave the title compound (0.11 g). [α]D=+18.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 137-139° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].CC([O-])=O.[Na+].I[CH:24]([CH3:26])[CH3:25]>C1COCC1>[Br:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH:24]([CH3:26])[CH3:25])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CC(C)I
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Yield: 7.6 %

Procedure:
Hydrazine hydrate (3.29 ml, 66.9 mmol) was added dropwise to a solution of 2-bromo-5-(chlorosulfonyl) benzoic acid (Preparation 22, 10.0 g, 33.4 mmol) in THF (100 mL) at 0° C. Once the addition was complete the mixture was allowed to warm to room temperature and the solid was collected by filtration. The solid was washed with heptane (3×20 mL) and dried under vacuum at 50° C. for 18 hours. The solid was dissolved in EtOH (100 mL) and NaOAc (16.4 g, 198 mmol) and 2-iodopropane (16.7 mL, 165 mmol) were added. The mixture was heated to reflux for 16 hours, cooled to room temperature and the solvent was evaporated under reduced pressure to leave an off-white solid. The solid was partitioned between EtOAc (50 mL) and 1M NaOH (100 mL). The aqueous layer was separated, acidified to pH=1 with 2M HCl and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to leave an orange oil. The oil was purified by silica gel column chromatography eluting with MeOH/CH2Cl2/AcOH 5:95.5:0.5 followed by a further chromatography eluting with heptanes/EtOAc 4:1 to give the title compound as a white solid 8% yield, 0.78 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([O:14][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:21]2[C:25](=[O:26])[NH:24][N:23]=[N:22]2)=[C:10]([F:27])[CH:9]=1.Br[CH2:29][CH2:30][CH2:31][F:32]>CN(C)C=O>[Cl:7][C:8]1[C:13]([O:14][C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][C:11]([N:21]2[C:25](=[O:26])[N:24]([CH2:29][CH2:30][CH2:31][F:32])[N:23]=[N:22]2)=[C:10]([F:27])[CH:9]=1
Reactant: O=c1[nH]nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A suspension of potassium carbonate (0.36 g), 1-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-1,4-dihydro-5-oxo-5H-tetrazole (0.54 g) and 1-bromo-3-fluoropropane (0.37 g) in N,N-dimethylformamide (10 ml) was stirred in an oil bath at 80° C. for 26 hours. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 2:1, to give the product, mp 111-3° C. 1H NMR (CDCl3, TMS): 2.30(2H, m), 4.20(2H, t, J=6.9 Hz), 4.59(2H, dt, J=46.9, 6.6 Hz), 7.13(1H, dd, J=4.8 Hz), 7.48(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.8 Hz), 8.58(2H, d, J=4.8 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:12]([O:25][CH3:26])[CH:11]=2)=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[I:1][C:2]1[CH:3]=[C:4]([NH2:27])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:12]([O:25][CH3:26])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C)nc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(C)nc1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
To a stirred suspension of 5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine (13.57 g, 26.80 mmol) in acetic acid (100 mL) was added iron powder (8.10 g, 145.0 mmol). The bright yellow suspension was gradually warmed to 90° C. After 30 min of heating, the dark brown reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (400 mL). The mixture was filtered through Celite with the aid of additional ethyl acetate (100 mL). The filtrate was then washed with water (2×150 mL) and 1N sodium hydroxide solution (2×200 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 6.97 g (55%) of 5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine as a brown solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=O)[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:23]([C:25]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=[S:26])[NH2:24].CN(C)C=O>Cl.O>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:24][NH:23][C:25]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[S:26])[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 80.2 %

Procedure:
1-[5-(4-n-Hexylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.117 mmol, 35.1 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.117 mmol, 24.7 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (46.3 mg, yield 80%).