Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])(=[O:22])=[O:21])[N:3]=1
Reactant: Brc1n[nH]c2ccncc12
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Cl)n1nc(Br)c2cnccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine (198 mg, 1,0 mmol) in 10 ml THF was added portion wise at 0° C. sodium hydride (101 mg, 4 mmol, 95%). After addition was complete, 2-chlorobenzenesulfonyl chloride (495 mg, 2.347 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of water. The product was extracted into ethyl acetate and the organic layer was washed with brine. The organic solvent was evaporated under reduced pressure to give 3-bromo-1-(2-chlorophenylsulfonyl)-1H-pyrazolo[4,3-c]pyridine as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1>[O-2].[Mn+4].[O-2].C(#N)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Cl)=NN1c1cccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)nn1-c1cccnc1
Temperature: 60 °C

Procedure:
In a preferred reaction, ethyl 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b) and acetonitrile are mixed with manganese(IV) oxide and the mixture is heated at about 60° C. until the reaction is completed. The ethyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)([CH3:23])[CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:14])=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:14])=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[OH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)([CH3:23])[CH3:22])=[CH:19][CH:20]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C#CCOc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 4-propargyloxybenzoyl chloride (17.86 grams, 0.092 moles) in 110 milliliters chloroform is added at room temperature over a 2 hour period to a solution of bisphenol A (9.13 grams, 0.040 moles) and triethylamine (15.0 milliliters, 0.018 moles) in 75 milliliters chloroform. After an additional 1.5 hours, the solution is washed with 5 percent aqueous sodium bicarbonate, then with 1N hydrochloric acid. The organic solution is dried and the solvent is removed by evaporation. The product is purified by recrystallization from a 1:1 solution of toluene in heptane. About 21 grams of product are obtained, reflecting a yield of about 96 percent. Nuclear magnetic resonance spectra confirm the identity of the product, and establish its purity. A dynamic scanning calorimetry run shows a melt endotherm at about 144° C. and a polymerization exotherm with a maximum at about 296° C. The heat of polymerization is about 713 joules/gram.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].CCN(C(C)C)C(C)C.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]([CH:39]=O)[CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]([NH:1][CH2:39][C:31]1[CH:30]=[N:29][C:38]2[C:33]([CH:32]=1)=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCCC(NCc1cnc2ccccc2c1)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the chlorhydrate salt of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate (1.177 g; 3.87 mmol; 1.0 equiv.) in anh. DCE (24 ml) was treated successively with DIPEA (1.35 ml; 7.75 mmol; 2.0 equiv.), quinoline-3-carbaldehyde (609 mg; 3.87 mmol; 1.0 equiv.), and NaBH(OAc)3 (1.150 g; 5.42 mmol; 1.4 equiv.). The resulting beige heterogeneous mixture was further stirred at rt, under nitrogen, for 2 h 45 min. DCM (50 ml) and a solution of aq. sat. NaHCO3 (35 ml) were then added. The organic layer was further washed with a solution of aq. sat. NaHCO3 (35 ml) and with brine (35 ml). The resulting yellow organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=10/1) afforded methyl 5-(2,6-dimethoxyphenyl)-5-((quinolin-3-ylmethyl)amino)-pentanoate as a yellow oil. LC-MS (conditions B): tR=0.66 min.; [M+H]+: 409.35 g/mol.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Na].[C:6](OC)(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>N>[C:6]([NH:1][C:2]([NH2:4])=[O:3])(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccncc1
Reactant: NC(N)=O
Agent: N
Agent: [Na]
Product: NC(=O)NC(=O)c1ccncc1

Procedure:
Urea (7.5 g., 0.125 mole) is suspended in liquid ammonia (250 ml.) in a round bottom flask fitted with an acetone/dry-ice condenser. Sodium pellets (2.9 g., 0.125 mole) are added and, after they have dissolved, methyl isonicotinate (12 g., 0.089 mole) is added to the mixture. The ammonia is allowed to evaporate from the mixture overnight. The yellow-tan residue is dissolved in water (150 ml.), the pH of the mixture adjusted to 5.5 with glacial acetic acid, and the precipitate which forms filtered, washed with water and air dried. It is then washed with hexane and triturated with boiling methanol. The white solid (isonicotinic acid) is removed by filtration and the filtrate evaporated to dryness to give the give the title product as a yellowish solid: m.p. 245°-247° C. Quantitative analysis and infra-red data are consistent with the values expected for the product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:23][CH2:22]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1cnc(N2CCNCC2)nc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(CCCCn3nnc4ccccc43)CC2)nc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-pyrimidinyl)piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.8 g compound (I-45) with a yield of 67.1%. ESI-MS [M+H]+: m/z 337.2.
Reaction SMILES: [C:1]([N:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)=[O:39].S(=O)(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:12][CH2:13][CH:14]([C:15](=[O:17])[NH:36][CH2:37][C:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[O:39])[CH2:18][CH2:19]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N-carbobenzoxy-isonipecotic acid (10.49 g, 39.84 mmol) and 4-methylmorpholine (NMM) (500 mL, 45.0 mmol) in anhydrous dichloromethane (200 mL) under N2 and cooled in an -25° C. bath is added isobutyl chloroformate (5.30 mL, 40.0 mmol) dropwise. Following complete addition, the suspension is stirred for 5 min, then 2-amino-4'-chloroacetophenone hydrochloride (7.4632 g, 36.217 mmol), prepared as in Part A, is added, followed by NMM (10.10 mL, 90.94 mmol). After stirring in the -25° C. bath for 30 min, the suspension is allowed to warm to RT over 1.5 h. To the solid reaction mixture is added half-saturated aqueous sodium bisulfate, dichloromethane, and ethyl acetate. The solids are collected, washed with dichloromethane, and heated to reflux in THF (300 mL) for 30 min. The mixture is filtered and the filtrate concentrated to about 1/20th volume. Diethyl ether is added, the precipitated solids are collected, and dried in vacuo at RT to afford the product as fluffy, white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of Compound 58 (5 g, 25 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 7.3 g (96%) of white solids. 1H NMR (DMSO-d6): δ 5.45 (s, 2H), 7.14-7.17 (m, 3H), 7.44 (m, 2H), 7.64 (dd, J=1.7, 8.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H).
Reaction SMILES: [N+:1](=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:12](N)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[C:12]([NH:1][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)C(=[N+]=[N-])C(C)=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)C(NC(=O)c1ccccc1)C(C)=O
Yield: 75 %

Procedure:
A solution of ethyl 2-diazo-3-oxobutanoate (20 g, 128 mmol) in 1,2-dichloroethane (100 mL) was added over 16 h to a refluxing solution of benzamide (13 g, 107 mmol) and dirhodium tetraacetate (1.4 g, 3.2 mmol) in 1,2-dichloroethane (200 ml). The mixture was evaporated in vacuo and purified by flash chromatography to give ethyl 2-benzamido-3-oxobutanoate as a yellow oil (20 g, 50% yield).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12])[CH2:3][OH:4]
Reactant: NC(C(=O)O)c1ccccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)c1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-2-(2-bromophenyl)acetic acid (4.89 g, 21.3 mmol) in THF (50 mL) was added dropwise a solution of LiAlH4 in THF (1.0 M, 42.5 mL, 42.5 mmol) at 0° C. under N2. The reaction was allowed to warm to ambient temperature and stirred for 4 hours. The reaction mixture was cooled to 0° C. and carefully quenched by dropwise addition of water (1.7 mL) followed by 15% NaOH solution (1.7 mL) and water (5.1 mL). The mixture was stirred at ambient temperature for 15 minutes and filtered through Celite. The filtrate was concentrated to give crude 2-amino-2-(2-bromophenyl)ethanol, which was used in the next step without further purification.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>C(O)(=O)C.O>[N:1]([CH2:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:3]
Reactant: CNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NCNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium nitrite, 5.9 g (0.086 moles), was added in 3 portions over a period of 30 minutes to a stirred solution of 18.9 g (0.071 m) of 3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 200 ml of acetic acid. After the addition was completed, the mixture was stirred for 20 minutes at room temperature and was then diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was crystallized from ether to yield product. Additional material was obtained from the concentrated mother liquors. For analysis, the material was recrystallized from ethyl acetate/hexane, mp 139°-140° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1ccccc1Cl)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.165 g (0.291 mmol) of (2R*,4S*)-2-benzyl-1-(2-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.044 g (1.16 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR75## is obtained (0.109 g, 80%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.33, MS: M+ =469, 471; IR: 3680, 1640, 1605, 1580 cm-1.
Reaction SMILES: Cl.[Cl:2][C:3]([O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:14]1([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[ClH:2].[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[C@@H:6]([O:5][C:3](=[O:4])[N:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7]2
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=C(Cl)OC1CN2CCC1CC2
Agent: Cl
Solvent: ClCCCl
Product: O=C(O[C@H]1CN2CCC1CC2)N(Cc1ccccc1)c1ccccc1

Procedure:
To a suspension of 750 mg (2.58 mmol) of 3-quinuclidyl chloroformate hydrochloride in 20 mL of 1,2-DCE, a solution of 395 mg (2.15 mmol) of N-phenylbenzylamine in 5 mL of 1,2-DCE was added dropwise. Once completed the addition, the mixture was refluxed for three hours. The reaction crude was allowed to cool down and the solvent distilled off under reduced pressure. The residue was purified by column chromatography (SiO2, eluent: CHCl3-methanol 10:1) yielding 720 mg (1.95 mmol) of a hygroscopic foam corresponding to the title compound. IR (KBr, cm−1): 3400-3200, 2700-2300, 1700 cm−1. 1H-RMN (CDCl3): 12.30 (s, 1H), 7.20-6.90 (m, 10H), 5.10 (m, 1H), 4.83 (m, 2H), 3.52 (m, 1H), 3.18 (m, 4H), 2.80 (m, 1H), 2.34 (s, 1H), 1.92 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.CS([CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)(=O)=O>>[CH3:26][N:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:16]2[CH:15]=[CH:14][C:13]([N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:31][C@H:32]5[CH2:36][CH2:35][CH2:34][O:33]5)[CH:3]=4)[C:8]3=[O:12])=[CH:18][CH:17]=2)[CH2:20][CH2:21]1
Reactant: CS(=O)(=O)C[C@H]1CCCO1
Reactant: CN1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)CC1
Product: CN1CCCN(c2ccc(N3CCc4cc(OC[C@H]5CCCO5)ccc4C3=O)cc2)CC1

Procedure:
6-Hydroxy-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one and (R)-2-methanesulfonylmethyl-tetrahydrofuran were reacted according to Method K1. In this way the product was obtained with molecular weight 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[H-].[Na+]>CN(C)C=O>[N:30]1([CH2:24][CH2:23][C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][N:2]([CH3:1])[S:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[CH2:18][CH2:19]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CN(C[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](CCn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-methanesulfonic acid 2-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-ethyl ester (example 9.10) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-[4-(2-imidazol-1-yl-ethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellowish solid, MS: 430 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][C@@H:52]1[CH2:57][NH:56][CH2:55][C@H:54]([CH3:58])[NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:56]3[CH2:55][C@H:54]([CH3:58])[NH:53][C@H:52]([CH3:51])[CH2:57]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and (2R,6S)-2,6-dimethylpiperazine (26.7 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (122.9 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [62.3 mg (51%)]. LC-MS m/z 769.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[BH4-].[Na+].Cl>C(Cl)Cl.CO>[OH:12][CH:7]1[C:6]2[C:11](=[C:2]([CH3:1])[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(c1C)SCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1C)SCCC2O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
30 g (0.127 mol) of methyl 8-methylthiochroman-4-one-7-carboxylate are dissolved in a mixture of 120 ml of methylene chloride and 60 ml of methanol and the solution is cooled to 0-5° C. 2.4 g (0.064 mol) of sodium borohydride are then added a little at a time. Stirring is continued at this temperature for one hour. 200 ml of 2N hydrochloric acid are added to the reaction solution. This gives two phases. The organic phase is separated off and dried and the solvent is distilled off. The crude product is further reacted directly without further purification.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:20]([OH:22])=[O:21])[CH2:13]3)[CH:10]=[CH:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClC(O[CH2:34][CH:35]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=O>O>[CH:37]1[C:36]2[CH:35]([CH2:34][O:5][C:6]([N:8]3[C:19]4[C:11](=[C:12]5[C:16](=[CH:17][CH:18]=4)[NH:15][CH:14]([C:20]([OH:22])=[O:21])[CH2:13]5)[CH:10]=[CH:9]3)=[O:7])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)O)C3
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1
Reaction time: 3 h
Yield: 84.4 %

Procedure:
3-(tert-Butyloxycarbonyl)pyrrolo[3,2-e]indoline-7-carboxylic acid 8 (Boger et. al, J. Org. Chem. 52:1521 (1987)) (0.76 g, 2.4 mmol) was deprotected by a treatment with 5 mL of TFA for 1 h. TFA vas evaporated and the resultant trifluoroacetate dissolved in a mixture of 11% Na2CO3 (10 mL) and 5 mL of THF. 9-Fluorenylmethyl chloroformate (0.75 g, 2.9 mmol) was added and the reaction mixture was stirred for 3 h. The reaction was diluted with water (200 mL) and extracted with ethyl ether (2×50 mL). The aqueous phase was acidified by adding 1N HCl to pH 1-2. Precipitated product was collected by centrifugation, washed with water and dried under vacuum to afford 0.86 g (83%) of 9 as a yellow-gray solid.