Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][C:2](C)(C)[CH3:3].[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(I)C>C1COCC1>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:2][CH3:3])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Cl)ccc21
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
t-BuLi (3.7 mL of 1.7 M solution in pentane) was added dropwise to a solution of N-(benzensulfonyl)-5-chloroindole (1) (J. Org. Chem. 1981, 46, 3859) (1.5 g, 5.14 mmol) in THF (35 mL) at −70° C., under a nitrogen atmosphere. The mixture was stirred for 15 min, allowed to warm to room temperature over 20 min, cooled to −70° C., and treated with a solution of ethyl iodide (0.84 mL, 10.5 mmol) in dry THF (5 mL). The mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, stirred for 2 h, poured into ice (15 g), and a saturated aqueous NH4Cl solution and then extracted with ether (3×20 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give a residue which was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from ethylacetate/cyclohexane.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]2([F:55])[CH:52]3[CH2:53][CH:48]4[CH2:49][CH:50]([CH2:54][CH:46]2[CH2:47]4)[CH2:51]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C:45]3([F:55])[CH:52]4[CH2:51][CH:50]5[CH2:49][CH:48]([CH2:47][CH:46]3[CH2:54]5)[CH2:53]4)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(F)C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(F)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.24 g, 74%): 1H NMR (300 MHz, CDCl3) δ8.77-8.65 (m, 1H), 7.63-7.56 (m, 1H), 6.68-6.58 (m, 1H), 4.30 (d, J=24.85 Hz, 2H), 3.42 (s, 3H), 2.34-2.16 (m, 4H), 2.14-2.01 (m, 1H), 1.97-1.85 (m, 4H), 1.84-1.72 (m, 4H), 1.72-1.62 (m, 2H), 1.00-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 438.1 (M−1).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16])([CH3:12])([CH3:11])[CH3:10].[CH:22](OCC#N)=[O:23]>ClCCl>[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:16][CH:22]=[O:23])([CH3:12])([CH3:11])[CH3:10]
Reactant: N#CCOC=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The preparation was performed in analogy to W. Duczek et al., Synthesis, 37-38 (1996). A solution of 4.04 g (40 mmol) of triethylamine in 10 mL of dichloromethane was added to a solution of 8.94 g (40 mmol) of L-leucine tert-butyl ester hydrochloride and 3.4 g (40 mmol) of cyanomethyl formate in 60 mL of dichloromethane at 0° C. The reaction solution was allowed to warm to room temperature, stirred at room temperature overnight, and then washed twice with saturated NaCl solution. The phases were separated and the organic phase was dried over magnesium sulfate. The residue obtained after filtration and removal of the solvent in vacuo was distilled in vacuo. Yield: 7.5 g (87%). Boiling point: 118° C./2.7 Pa (0.02 torr).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:5]2=[C:4]([C:21]2([OH:34])[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:3]=1.[Si](I)(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:21]2([OH:34])[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc(Cl)nc21
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: OC1(c2cc(Cl)nc3[nH]ccc23)CCNCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
To tert-butyl 4-(6-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-hydroxypiperidine-1-carboxylate (510 mg, 1.00 mmol) in CH2Cl2 (6 mL) was slowly dropwise added TMS-I (0.43 mL, 3.01 mmol) at rt, and stirred at 60° C. overnight. Partial of the solvent was removed on rotary vacuo, and the residue was purified on reverse phase PrepHPLC to afford the expected product, 4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol (310 mg, 63%), as a dark brown solid. 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 2.02 (d, J=14.35 Hz, 2 H) 2.65-2.76 (m, 2 H) 3.42 (d, J=11.33 Hz, 2 H) 3.58 (d, J=11.83 Hz, 2 H) 4.61 (s, 2 H) 6.91 (d, J=3.53 Hz, 1 H) 7.13 (s, 1 H) 7.28 (d, J=3.53 Hz, 1 H); Mass spec. 252.05 (MH+) calc. for C12H14ClN3O 251.08.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])C.[OH-].[Na+].C(Cl)(Cl)Cl.CO>C(O)C>[C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])([OH:5])=[O:3]
Reactant: C#Cc1cccc(C2C(C(=O)OCC)=C(C)NC(C)=C2C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#Cc1cccc(C2C(C(=O)O)=C(C)NC(C)=C2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
In 80 ml of ethyl alcohol was dissolved 7.5 g (0.02 mol) of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-ethynylphenyl)pyridine obtained in Example 2. Thereto was added 20 ml of 5N sodium hydroxide. After stirring for 24 hours at room temperature, the mixture was reacted further for 30 hours at 40°-45° C. After completing the reaction, the reaction solution was distilled away under reduced pressure. Water and chloroform were added to the residue, and a water layer was collected. The water layer was acidified with concentrated hydrochloric acid to give precipitate. The precipitate was purified by subjecting to silica gel column chromatography [eluent: chloroform-methyl alcohol (100 : 5)]to give 1.5 g of the desired compound (yield: 23.1%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3ccccc3c2)cc1
Temperature: 120 °C
Yield: 95.2 %

Procedure:
28.2 g (200 mmol) of β-naphthol and 30.4 g (220 mmol) of potassium carbonate were mixed in 80 ml of dimethylformamide, 27.8 g (220 mmol) of benzyl chloride were added dropwise, and the mixture was heated at 120° C. for 2 hours. The residue formed was filtered off, and the filtrate was admixed with water to the onset of cloudiness. Filtration of the cold mixture and drying of the solid gave 44.6 g (95%) of β-naphthyl benzyl ether; melting point: 101° C.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[NH2:8][C:7]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: NNc1ccccc1
Reactant: CC(C)(C#N)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Temperature: 60 °C
Yield: 53.9 %

Procedure:
To a solution of 2,2-dimethyl-3-oxopentanedinitrile (500 mg, 3.7 mmol) prepared as described in Example 125A Step 1, in anhydrous EtOH (33 ml) was added phenylhydrazine hydrochloride (763 mg, 3.7 mmol) and the reaction mixture was heated at 60° C. for 2 h. The solvent was removed under reduced pressure and the residue taken in EtOAc, washed with water and brine and the organics combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to afford 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (451 mg, 54%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.76 (s, 6H), 3.84 (brs, 2H), 5.69 (s, 1H), 7.26-7.57 (m, 5H); LC-MS (ESI) m/z 227 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(OC)ccc2cccc(Cc3ccccc3)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
79.5 g of 8-benzyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 300 ml of acetone to give a solution. 120 ml of 6N hydrochloric acid was added to the solution at room temperature. The obtained mixture was stirred for 1.5 hours, followed by the addition of 400 ml of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The obtained solid was washed with hexane/ diisopropyl ether (1:1) to give 51 g of the title compound as a colorless crystal.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[NH2:41])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[NH:41][C:18](=[O:20])[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](N)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 8 ml of DMF were dissolved 808 mg of benzoyl-L-phenylalanine and 2.05 g of Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester trifluoroacetate, after which 681 mg of DCC, 405 mg of HOBt and 304 mg of TEA were added thereto with ice-cooling, and the mixture was stirred for 3 hrs, and then at room temperature for a further 24 hrs. After the reaction, the DCU thus precipitated was removed by filtration, and ethyl acetate was added to the filtrate, after which the mixture was washed with 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue thus obtained was recrystallized from chloroform-diethyl ether to obtain 1.4 g (yield 57%) of benzoyl-L-phenylalanyl-Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester, m.p. 177°-185° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][N:21]=[C:22]3[NH2:25])=[CH:17][CH:16]=2)[C:10]1=[O:26].C(N(C(C)C)CC)(C)C.[S:36]1[C:44]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[S:45](Cl)(=[O:47])=[O:46].O>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:25][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][S:45]([C:37]4[S:36][C:44]5[C:39](=[N:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)(=[O:46])=[O:47])[C:10]3=[O:26])[CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Nc1nccc2ccc(CN3CC[C@@H](N)C3=O)cc12
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nccc2ccc(CN3CC[C@@H](NS(=O)(=O)c4cc5ncccc5s4)C3=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(R)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)pyrrolidin-2-one trifluoroacetate (80 mg, 0.216 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) are dissolved in acetonitrile (12 mL), and stirred at room temperature for 15 minutes before adding thieno[3,2-b]pyridine-2-sulfonyl chloride dropwise as a solution in acetonitrile (8 mL). The reaction mixture is left at room temperature overnight, water (4 mL) added, and the solution concentrated in vacuo to remove the acetonitrile (ca. 4 mL of solution). 75% Acetonitrile/water (4 mL) is added. and the product purified by reverse phase preparative HPLC with gradient elution 10-40% acetonitrile/water (0.1% trifluoroacetic acid). The product fractions are combined, the acetonitrile removed in vacuo, and the aqueous solution lyophilized to give the product as a white powder (52 mg, 0.092 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC)(OC)C(=O)Nc1ccc(Br)cc1C
Yield: 50 %

Procedure:
4-Bromo-2-methylaniline (2.83 grams, 0.01 mole), methyl chlorocarbonyl(dimethoxy)acetate (2.99 grams, 0.01 mole), prepared in Part A, and triethylamine (1.54 grams, 0.015 mole) were reacted in a manner similar to the procedure described in Example I to give 1.73 grams (0.005 mole) of methyl 3-[(4-bromo-2-methylphenyl)amino]-2,2-dimethoxy-3-oxopropanoate having a melting point of 99° C.-103° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:11]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of tert-butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]-carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction solution was concentrated and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 221.26 (C11H15N3O2); MS (ESI): 222 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][CH:53]([C:56]#[N:57])[CH2:52][CH2:51]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:56]([CH:53]1[CH2:54][CH2:55][N:50]([CH2:46][C:42]2[CH:41]=[C:40]([C:35]3[C:36]([F:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]5[C:11]([NH:12][CH:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)=[C:6]6[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]6=[N:8][C:9]=5[CH2:48][CH3:49])=[O:22])[CH:24]=4)=[O:30])[CH:34]=3)[CH:45]=[CH:44][CH:43]=2)[CH2:51][CH2:52]1)#[N:57]
Reactant: N#CC1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCC(C#N)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28.1 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (82 mg, 0.129 mmol) in DCM (2.58 mL) was added 4-piperidinecarbonitrile (14.21 mg, 0.129 mmol), NaBH(OAc)3 (41.0 mg, 0.193 mmol). This mixture was stirred at room temperature for 19 h. The reaction mixture was washed with H2O (1 mL), concentrated, purified using a Gilson HPLC (with 0.1% TFA), and basified with an amine cartridge to afford 0.0274 g (28%) of the title compound. LC-MS m/z 757 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.53 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.82-1.93 (m, J=13.05 Hz, 2 H) 1.96-2.38 (m, 6 H) 2.92-3.20 (m, 4 H) 3.22-3.29 (m, 1 H) 3.49-3.73 (m, 4 H) 4.00-4.09 (m, 2 H) 4.31-4.52 (m, 5 H) 4.62 (s, 2 H) 4.72 (s, 2 H) 7.20 (dd, J=10.54, 8.53 Hz, 1 H) 7.39-7.46 (m, 1 H) 7.50-7.65 (m, 4 H) 7.67-7.77 (m, 2 H) 8.05 (d, J=8.03 Hz, 2 H) 8.30 (s, 1 H) 8.39 (t, J=1.51 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([Br:11])=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[CH2:13]=[CH2:14].[O-]Cl.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]2[CH2:14][CH2:13][O:7][N:6]=2)[C:8]([Br:11])=[CH:9][CH:10]=1
Reactant: Cc1c(Br)ccc(Br)c1C=NO
Reactant: C=C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1c(Br)ccc(Br)c1C1=NOCC1
Reaction time: 8 h

Procedure:
68 g (0.23 mol) of 3,6-dibromo-2-methylbenzaldoxime are dissolved in 750 ml of methylene chloride in a pressure container. 20 g of ethylene are applied, and 620 g of a 12.5% strength solution of NaOCl are then pumped in at room temperature, and the mixture is stirred overnight. The pressure vessel is vented, and the organic phase is then separated off, washed once with 250 ml of water and dried, and the solvent is removed under reduced pressure. This gives 77 g of product (95% pure) (99% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12](SC)[NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:10])=[O:9].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[N:25][OH:26])(=[O:10])=[O:9]
Reactant: NO
Reactant: CSC(=NS(=O)(=O)c1ccccc1Cl)Nc1nc(C)cc(C)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=NO)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 0.5 g of methyl N'-(2-chlorophenylsulfonyl)-N-(4,6-dimethylpyrimdin-2-yl)carbamimidothioate in 10 ml of tetrahydrofuran was added 0.3 g of hydroxylamine hydrochloride and 0.3 g of sodium acetate. The mixture was stirred at room temperature for 2 hours, whereupon the product was precipitated with ice-water, filtered, washed with water, and dried by suction to afford 0.3 g of the title compound, m.p. 165°-167°. NMR (CDCl3 /DMSO-d6) δ2.6 (s, 6), 6.8 (s, 1), 7.4 (m, 3), 8.2 (m, 1), 10.2 (br, 1), 12.0 (br, 1), m/e: 355 (M+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:18][N:19]3[CH2:23][CH2:22][N:21]=[CH:20]3)[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Br>CO.C(O)(=O)C>[N:19]1([NH:18][C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]3[C:11]=2[CH2:10][CH2:9][NH:8]3)[CH2:23][CH2:22][N:21]=[CH:20]1
Reactant: Cc1ccc(NN2C=NCC2)c2c1N(C(=O)OC(C)(C)C)CC2
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NN2C=NCC2)c2c1NCC2
Yield: 97.4 %

Procedure:
1-t-Butoxycarbonyl-2,3-dihydro-4-(2-imidazolinylamino)-7-methylindole (0.384 g, 1.22 mmol) is dissolved in methanol (10 mL). To this solution is added 30% hydrogen bromide in acetic acid (2.5 mL). The solution is heated to reflux for 2.5 hours. The reaction mixture is concentrated by rotary evaporation and the resulting orange liquid taken up in chloroform. The chloroform solution is treated with 50% NaOH solution and extracted with three 25 mL portions of chloroform. The organic layers are collected and dried over anhydrous potassium carbonate. Filtration and removal of the solvent produces a brownish-orange solid which is purified via silica gel column chromatography using 10% methanol (ammonium hydroxide treated)/methylene chloride as the eluent to afford 0.257 g of 2,3-dihydro-4-(2-imidazolinylamino)-7-methylindole as a light-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-methoxyquinoline (Intermediate 58) (400 mg, 2.51 mmol), potassium nitrate (330 mg, 3.26 mmol) and conc. H2SO4 (1.2 ml) gave the title compound (250 mg, 50%) after purification by column chromatography with n-hexane/EtOAc (3:1) as the eluent.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([N:23]3[CH2:22][CH2:21][N:20]([C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[F:13])[CH2:25][CH2:24]3)=[O:27])[CH2:33][CH2:32]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2F)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
Phenylsulphonyl chloride (0.38 g) was added to a mixture of 1-[(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine dihydrochloride (0.65 g) and triethylamine (1.5 ml) in dichloromethane (30 ml) at 5° C. The solution was stirred at 5° C. for 1 hour and at ambient temperature for 18 hours. The solution was evaporated to dryness. The residue was dissolved in dichloromethane (100 ml), and the solution was washed with water (3×10 ml), dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) using 0.1-0.3% methanol in dichloromethane as eluent. Recrystallisation from ethyl acetate/isohexane gave 1-phenylsulphonyl-4-[1-(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine (0.49 g), as an off-white solid mp 143-145° C: NMR (CDCl3): 3.05 (t, 4H), 3.25 (t, 4H), 3.40 (m, 8H), 6.70 (dd, 1H), 7.60 (m, 3H), 7.78 (s, 2H), 8.20 (dd, 2H); m/z 434 (M+1).