Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6]1[CH:7]=[C:8](/[C:12](/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)#[N:2].C([O-])(=[O:33])C.[Na+]>Cl>[C:1]([N:3]=[C:4]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6]1[CH:7]=[C:8](/[C:12](/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)(=[O:33])[NH2:2]
Reactant: CC(C)CNC(=NC#N)Nc1cccc(/C(=C\CCCC(=O)O)c2cccnc2)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)CNC(=NC(N)=O)Nc1cccc(/C(=C\CCCC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.34 g of 5E-6-(3-(2-cyano-3-(2-methylpropyl)guanidino)phenyl)-6-(3-pyridyl)hex-5-enoic acid are dissolved in 50 ml of 4N hydrochloric acid and stirred for 48 hours at ambient temperature. The solution is adjusted to pH 5-6 by the addition of sodium acetate and extracted with ethyl acetate. The organic extract is evaporated down and the residue is purified over a silica gel column with dichloromethane/ethanol=19:1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]1[C:12]2[CH:13]=[CH:14]C=CC=2N=C1>>[O:8]1[CH2:12][CH:13]1[CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1cccnc1
Product: c1cncc(OCC2CO2)c1

Procedure:
Compound 73 was prepared in the manner of compound 6 substituting 3-hydroxypyridine for compound 8 in part C-5 of Example 1.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:35]([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH3:36]>CN(C=O)C>[CH:38]1([N:37]([CH2:35][CH3:36])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)=[O:3])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(COc1cccc2c1CCC(=O)N2)CC(=O)O
Reactant: CCNC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(C(=O)CC(C)COc1cccc2c1CCC(=O)N2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.3 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 0.8 ml of triethylamine are added to 50 ml of DMF, and the mixture is added dropwise with 0.65 ml of isobutyl chloroformate under external ice cooling and agitation at internal temperature of 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added dropwise with 0.7 g of N-ethylcyclohexylamine and further agitated at room temperature for 2 hours. The solvent is distilled off and the residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, aqueous K2CO3 solution and water in that order and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene to obtain 0.8 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 114°-115.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([NH:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1CN
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CNc1nccnc1N
Yield: 19.7 %

Procedure:
A mixture of 2-amino-3-chloropyrazine (4.3 g), 2-methylbenzylamine (4.6 g), potassium carbonate (5.5 g), and potassium iodide (0.4 g) in N,N-dimethylformamide (43 ml) was refluxed for 24 hours under a nitrogen atmosphere and allowed to stand at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (110 g) with a mixture of chloroform and methanol (100:3) as an eluent to give 2-amino-3-(2-methylbenzylamino)pyrazine (1.4 g).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[CH:16][N:15]=1.[CH3:28][O:29][CH2:30][C:31]1[C:38]([F:39])=[C:37]([F:40])[C:34]([CH2:35]O)=[C:33]([F:41])[C:32]=1[F:42]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:23][CH2:35][C:34]2[C:33]([F:41])=[C:32]([F:42])[C:31]([CH2:30][O:29][CH3:28])=[C:38]([F:39])[C:37]=2[F:40])=[O:22])=[CH:16][N:15]=1
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Reactant: Cc1ncc(C(C(=O)O)C(C)(C)C)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCc1c(F)c(F)c(COC(=O)C(c2cnc(C)nc2)C(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.276 g) in dry dichloromethane (6 cm3) was added to a stirred solution of (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoic acid (0.3 g) and 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzylalcohol (0.33 g) containing a catalytic amount of 4-(N,N'-dimethylamino) pyridine. The stirred mixture was maintained at the ambient temperature for 2 hours, and left to stand overnight. The reaction solution was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel using a 1:1 (by volume) mixture of ethyl acetate and dichloromethane as eluent to give 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoate (0.228 g) as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13]O.O>CC1C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[CH3:5][C:3]1([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[O:15][CH:12]([CH2:11][Cl:10])[CH2:13][O:4]1
Reactant: OCC(O)CCl
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC1(C)OCC(CCl)O1
Yield: 71.9 %

Procedure:
In a similar manner to the preceding Examples, 65 g (0.5 mol) of ethyl acetoacetate are heated together with 55 g (0.5 mol) of 3-chloro-1,2-propanediol and 0.2 g of p-TSA in a water separator. 100 ml of hexane act as entraining agent. Once 9 ml of water have separated, the reaction mixture is washed with 100 ml of water, to which 1 g of NaOH is added, dried over Na2SO4 and fractionated. 80 g (72%) of 2-methyl-2-ethoxycarbonylmethyl-4-chloromethyl-1,3-dioxolane are obtained. Bp.: 124° C. (1500 Pa); IR: 1736 cm−1 (C═O, ester); MS: m/e=207 (M−15), 181, 173, 157, 144, 135, 115, 99, 75, 57, 43.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>CCO.N1CCCCC1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(F)cc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(F)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
5-amino-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-fluorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:15])([CH3:3])=[CH2:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.[I-]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N:6]2[C:7]3[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:15])=[CH:24]1
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: C=C(C)n1c(=O)[nH]c2cc(C)c(C)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-Isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.25 g, 1.2 mmol) in DMF (10 mL) was added K2CO3 (0.51 g, 3.7 mmol). The reaction mixture was heated to 90° C. and stirred for 20 min. (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium; iodide (0.64 g, 1.8 mmol) was then added to the reaction mixture and stirred for another 3 h. The reaction mixture was treated with ethyl acetate and washed with water. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 0.35 g the desired product as an off-white solid. LCMS (ESMS): m/z 360.33 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCNC(=O)C2
Temperature: 120 °C
Yield: 46.2 %

Procedure:
7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (50 mg, 0.2 mmol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (90.5 mg, 0.27 mmol), and a 4 M solution of hydrogen chloride in dioxane (0.1 mL, 2 eq), were added to 2-methoxyethanol (2 mL), and the reaction mixture was heated for 6 hours at 120° C. The reaction mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and then concentrated on SiO2. Flash chromatography on SiO2 (MeOH/dichloromethane 0-5%) gave N-{(1R,2R)-2-[5-Chloro-2-(8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (47 mg, 30%) as a beige solid. MP: 109-115° C.; 1H-NMR (CDCl3) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.18 (m, 1H), 6.00 (d, J=6.5 Hz, 1H), 5.51 (d, J=7.8 Hz, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 3.75 (m, 2H), 3.53 (m, 2H), 3.25 (m, 1H), 3.04 (t, J=6.1 Hz, 2H), 2.85 (s, 3H), 2.60 (s, 2H), 2.20 (m, 2H), 1.8 (m, 2H), 1.34 (m, 2H); LC/MS (ESI+): 509.28 (M+H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[CH2:16](O)[CH2:17][CH3:18]>S(=O)(=O)(O)O>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([O:3][CH2:16][CH2:17][CH3:18])=[O:2]
Reactant: O=C(O)c1cc(=O)c2cc(O)ccc2o1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)c1cc(=O)c2cc(O)ccc2o1

Procedure:
14.14 g (49.2 mmoles) of 2-carboxy-6-hydroxy-4-oxo-4H-1-benzopyran is dissolved in 200 ml of n-propanol and 1 drop of concentrated sulfuric acid is added. The mixture is refluxed for 30 hours, concentrated. The resulting solid is suspended in water, neutralized with sodium bicarbonate and filtered, washing the solid with water, then drying. This gives 10.6g of 2-carbo-propoxy-6-hydroxy-4-oxo-4H-1-benzopyran as a solid which is purified by recrystallization from n-propanol/acetone or by HPLC.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of 0.75 g (2.68 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.07 g (10.4 mmol) of 2-methylpiperazine and 30 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water/ethanol and acetonitrile, and dried in vacuo to give 0.42 g of the title compound, mp 189°-192° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:34]2[CH2:39][CH2:38][S:37][CH2:36][CH2:35]2)=[O:20])[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]1
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
1.28 g (2.73 mmol) of the compound from Example 88A, 1.41 g (13.6 mmol) of thiomorpholine and 1.13 g (8.18 mmol) of potassium carbonate were added to 18 ml of DMF, and the mixture was heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 40 minutes. For workup, the reaction solution was concentrated by rotary evaporation, and the residue was admixed with water. After addition of ethyl acetate and phase separation, the organic phase was washed with aqueous 1 N hydrochloric acid solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. This gave 946 mg of crude product in 72% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [CH2:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:3]([CH2:4][CH3:5])([CH3:6])[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: CCC(C)(CC)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(C)(CC)c1ccc(Cl)nn1

Procedure:
To 34 g. of 6-(1-ethyl-1-methylpropyl)-3-pyridazinone was added 175 ml. of phosphorus oxychloride, and the mixture was stirred under reflux for 30 minutes. It was then cooled, excess phosphorus oxychloride was removed under vacuum, and the residual oil was poured into ice water. The residue was made basic to pH 9 with ammonia, and triturated. The aqueous mixture so prepared was extracted with two one-liter portions of diethyl ether, and the combined organics were dried and evaporated under vacuum to obtain 35 g. of the desired product, identified by mass spectroscopy, which showed a molecular ion having a weight of 198.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]#[N:22]>>[C:21]([CH2:20][N:5]1[C:6]2[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]1[CH2:2][CH2:3]1)#[N:22]
Reactant: N#CCBr
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#CCn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 62 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and bromoacetonitrile: MS (ES) m/z 290 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:29][CH2:30][C@H:31]([OH:41])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[OH:41][C@H:31]([CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH2:30][NH:29][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Product: O=S(=O)(Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1ccc(-c2ccccn2)s1

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 227) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.90 (m, 2H), 2.40-2.80 (m, 5H), 3.50-3.60 (m, 2H), 3.70-3.90 (m, 3H), 4.99 (brs, 1H), 6.66 (d, J=8.0 Hz, 2H), 6.75 (d, J=8.0 Hz, 2H), 6.83 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 1H), 7.36 (dd, J=4.4, 1.7 Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.88 (dd, J=8.0, 1.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.54 (d, J=4.4 Hz, 1H), 8.89 (s, 1H); MS (ES) m/z: 580.9 (MH+); HRMS Calcd. for C29H33N4O5S2 (MH+): 581.1892. Found: 581.1910.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.O.[NH2:32][NH2:33]>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:32][NH2:33])=[O:30])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Yield: 63 %

Procedure:
A mixture of 3.2 parts of phenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate, 50 parts of hydrazine hydrate and 100 parts of 1,4-dioxane is stirred and refluxed for 3 hours. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from N,N-dimethylformamide, yielding 1.7 parts (63%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide; mp. +300° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[NH2:27][CH2:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=3)[N:5]=[C:4]([N:14]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: NCC1(N)COC1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(CO)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.08-8.05 (d, J=11.2 Hz, 2 H), 7.94-7.92 (d, J=7.2 Hz, 1 H), 7.74-7.68 (m, 3 H), 7.57-7.53 (t, J=7.6 Hz, 1 H), 6.26 (s, 1 H), 5.31 (s, 2 H), 4.72 (s, 2 H), 44.57 (s, 4 H), 4.44 (s, 1 H), 3.88 (s, 2 H), 3.77-3.71 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:19].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:23][CH:22]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: Oc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(Oc3ccc(Cl)c(Cl)c3)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.45 g of 2-chloro-4-(3,4-dichlorophenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.22 g of p-methylbenzylchloride in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 4-methyl-1-[2-chloro-4-(3,4-dichlorophenoxy)phenoxy]methylbenzene. Yield, 81%. nD27 :1.6029