Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1)OCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(C(=O)N(Cc2ccccc2)c2ccc(Cl)cc2)cc1)OCC

Procedure:
To a solution of 0.50 g of 4-diethoxyphosphinylmethyl-N-(4-chlorophenyl)benzamide in 10 ml of dry THF was added in portions 0.07 g of sodium hydride (60%, in oil) under ice-cooling with stirring. After stirring for 30 minutes under ice cooling, a solution of 0.23 g of benzyl bromide in 2 ml of dry THF was added. After stirring for 5 hours at room temperature, 30 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-benzyl-N-(4-chlorophenyl)benzamide. It was recrystallized from benzene-n-hexane to give 0.40 g of colorless columnar crystals.
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13]>>[CH3:5][C:2]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][O:8][CH3:7])([CH3:6])[C:3]#[CH:4]
Reactant: C#CC(C)(C)Cl
Reactant: CCNCCOC
Product: C#CC(C)(C)N(CC)CCOC

Procedure:
In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne and N-(2-Methoxyethyl)ethylamine were converted to yield (1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine as colorless oil, MS: 170 (MH+).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[CH:28]1[CH2:33][C:32](=[O:34])[CH:31]=[CH:30][CH2:29]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[C@H:28]1[CH2:29][C@H:30]([CH3:2])[CH2:31][C:32](=[O:34])[CH2:33]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a 0° C. solution of dimethyl copper lithium (2.47 mmole) in ether (3 ml) and hexane (2 ml) was added dropwise a solution of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-cyclohexen-1-one (500 mg, 1.24 mmole) in ether (1.5 ml). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium chloride (300 ml). The quenched reaction was extracted with three 50 ml portions of ether, the combined ether extracts washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 475 mg (92%) of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=4)[N:27]=[CH:26][C:25]=3[O:24][CH2:23]2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([CH2:21][N:18]3[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]3)[CH2:35][C:34]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(N)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.2 %

Procedure:
Trifluoroacetic acid (1.25 mL, 16.10 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-yl-carbamic acid tert-butyl ester (540 mg, 1.07 mmol, 1.0 eq) in dichloromethane (15 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-ylamine as an orange viscous oil (400 mg, 97% yield).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([C:5]3[CH:16]=[N:15][NH:14][C:6]=3[C@H:7]2[C:10]([O:12][CH3:13])=[O:11])[N:3]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:13][O:12][C:10]([C@@H:7]1[C:6]2[N:14]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]=[CH:16][C:5]=2[C@H:4]2[CH2:9][N:8]1[C:2](=[O:1])[N:3]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@@H]1c2[nH]ncc2[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1ncc2c1[C@@H](C(=O)OC)N1C[C@H]2N(OCc2ccccc2)C1=O
Temperature: 50 °C
Yield: 11.8 %

Procedure:
0.2 g of the product obtained in Stage K of Example 1 is dissolved in 2 ml of acetonitrile, in a round-bottomed flask. 0.150 μl of ethyl bromoacetate and 240 μl of DIEA are added. The medium is heated at 50° C. for 24 hours and then the reaction medium is extracted with ethyl acetate, the organic phase is washed with an aqueous tartaric acid solution at 10% and then with an aqueous NaCl solution. The organic phase is dried over magnesium sulfate, filtered off and the solvent is evaporated off under reduced pressure. 266 mg of the crude product are obtained which are purified by chromatography on silica, eluting with a methylene chloride/acetone/triethylamine, 95/0.5/0.1%, mixture. 37 mg of the isomer A, ethyl trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-1-acetate having the empirical formula C20H22N4O6 are obtained (M=414.42 g).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:46])[CH2:36][CH2:37]5)=[O:34])=[C:28]([F:47])[CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)C1
Reaction time: 120 h
Yield: 25.2 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) and triethylamine (0.259 ml) at room temperature, followed by stirring for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (24.0 mg, 25%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:31]>>[NH2:31][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:3]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 24 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine with ammonia followed by purification on a silica gel column using ethyl acetate/toluene=8:2 as eluant.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: F[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3.06 g, 9.24 mmol) in THF (30 ml) was added 1.0M solution of tetrabutylammonium fluoride in THF (37.0 ml, 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature, water (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH2Cl2/MeOH: 50/1) to afford 1.18 g (71%) of brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH:41]([CH3:45])[CH2:42][CH2:43]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:43][CH2:42][CH:41]([O:40][CH3:39])[CH3:45])[CH:3]=1
Reactant: COC(C)CCO
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCC(C)OC
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (1.715 g, 6 mmoles; prepared according to Preparation 1B), triphenylphosphine (1.58 g, 6 mmoles), 3-methoxy-1-butanol (0.62 g, 6 mmoles) in dry tetrahydrofuran (50 ml) was treated dropwise with diethyl azodicarboxylate (1.1 g of 95% purity material, 6 mmoles). The solution was left to stir overnight. After evaporation of the solvent the residue was dissolved in methylene chloride. The solution was washed with 0.4N NaOH, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100), methanol (2.5), ammonium hydroxide (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated. The residue (1.7 g) was crystallized from toluene to yield 1.17 g (52%) of the title compound, m.p. 76°-78° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CS(C)=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (805.4 g), 2-methylimidazole (1101.7 g) and dimethyl sulfoxide (2416 mL) was stirred at 110° C. for 8 h and water was added to the obtained mixture. The mixture was extracted with ethyl acetate and the extract was washed with 5% brine. The solvent was evaporated and the residue was dissolved in ethyl acetate (1611 mL) with heating. n-Heptane (4832 mL) was added at 30° C. The precipitated crystals were collected by filtration and washed with ethyl acetate-n-heptane (1:3) to give the title compound (716.6 g, yield: 77.2%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[OH:13])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=2)[N:30]=1>CC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=3)[N:30]=2)[CH:15]=1)[OH:13])(=[O:3])[CH3:2]
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: CC(=O)c1ccccc1CCC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1CCC(O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Yield: 93.8 %

Procedure:
A mixture of the phenol of Step 4 (3.322 g, 12.3 mmol), K2CO3 (4.08 g, 29.5 mmol) and 2-(bromomethyl)-7-chloroquinoline (3.771 g, 14.7 mmol) in 60 mL of acetone was heated to reflux for 8 h. CD2Cl2 (100 mL) was added and the mixture was filtered through silica with EtOAc. Flash chromatography of the residue on silica using EtOAc:toluene 15:85 and 20:80 afforded 5.145 g (94%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1>C1COCC1>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[N:3][N:4]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2nnc(Cl)c3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine (0.50 g, 2.46 mmol) in THF (5 mL) are added 4-fluoro-benzyl zinc chloride (0.5M in THF) (6.40 mL, 3.20 mmol) and palladium tetrakis triphenylphosphine (0.36 g, 0.31 mmol). The mixture is degassed and stirred at 50° C. overnight. Then the reaction mixture is cooled down to room temperature, sat. NaHCO3 and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/Hexane: 10%˜40%) to give 1-chloro-4-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-phthalazine (compound 10f) (0.51 g, 30%). m/z=277.11 [M+1]
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].Cl>O.C(O)C>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)COc1ccc(-c2ccc(OCCCCCCO)cc2)cc1

Procedure:
4.5 g of KOH and 15 g of 4-hydroxy-4'-(2-methylbutoxy)-biphenyl are dissolved in 150 ml of a 1:1 water/ethanol mixture, the solution is raised to the boil and 9 g of 6-chloro-1-hexanol are slowly added dropwise, whilst stirring, after which the batch is refluxed for about 10 hours. When the reaction solution has cooled, it is acidified with HCl and the product is extracted with CHCl3 in a separating funnel. The CHCl3 is then stripped off and the crude product is recrystallized from ethanol (melting point 118° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>CCOCC>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:19]([O:18][CH3:17])=[O:20])(=[O:29])=[O:28])=[O:32])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(COC2CCCCO2)nc(N)n1
Solvent: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC2CCCCO2)n1
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3.25 g of the product from Example 3 in 50 ml of ether was added 3.75 g of 2-methoxycarbonylbenzenesulfonyl isocyanate and the mixture was stirred for 3 hours under nitrogen. The precipitated product was filtered and washed with ether to afford 6.0 g of the title compound, m.p. 126°-128°(d).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[NH2:22][NH2:23]>>[NH:22]([C:2]1[CH:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1)[NH2:23]
Reactant: CC1(C)OC(=O)N(c2ccnc(Cl)c2)[C@H]1c1ccccc1
Reactant: NN
Product: CC1(C)OC(=O)N(c2ccnc(NN)c2)[C@H]1c1ccccc1
Temperature: 140 °C

Procedure:
A mixture of (S)-3-(2-chloropyridin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1.44 g, 4.76 mmol) and anhydrous hydrazine (7.46 mL, 238 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) was heated at 140° C. for 15 minutes. LC-MS indicated complete consumption of starting material with the desired product as the major product. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-3-(2-hydrazinylpyridin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one. m/z (ESI) 299.2 (M+H)+.
Reaction SMILES: Cl.Cl[CH:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[N:14]1([CH:3]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: ClC1CCCCc2cccnc21
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCCCC2N1CCCC1
Reaction time: 5 h

Procedure:
5 g of 9-chloro-6,7,8,9-tetrahydro-5H -cyclohepta[b]pyridine hydrochloride were dissolved in 12.5 ml of water and 8 ml of pyrrolidine were added. The mixture was refluxed with vigorous stirring for 5 hours and the excess pyrrolidine was evaporated off under reduced pressure. 25 ml of a saturated solution of sodium bicarbonate and then 50 ml of water were added followed by extraction with methylene chloride. The combined organic phases were washed with water, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and methanol (9-1) to obtain 2.25 g of the expected product with an Rf=0.20. 2.25 g of the product were crystallized from petroleum ether (b.p. 40°-70° C.) to obtain 2 g of the expected product melting about 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCOCC1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(tetrahydro-pyran-4-yl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as yellow oil. MS: m/e=453.3 [M+H+].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:15])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:15])[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Ethyl chloroformate (15.91 g) was added dropwise to a solution of 4-bromo-2-fluoroaniline (25.33 g) and pyridine (21.06 g) in methylene chloride (260 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, it was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from ethyl acetate-n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-2-fluorophenyl)carbamate (34.45 g).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 56 %

Procedure:
As described for example 344 g, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 56%) which was obtained as a white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl.[Cu]=O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: Brc1ccccc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(c2cn(-c3ccccc3)c3ccccc23)CC1
Yield: 77.5 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)indole (10.0 g), bromobenzene (6.48 g), potassium carbonate (5.70 g) and copper(II) oxide (0.26 g) in anhydrous N,N-dimethylformamide (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and diluted with chloroform, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was subjected to column chromatography on alumina (400 g) followed by elution with a mixture of toluene and ethyl acetate (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure to give 3-(1-acetyl-4-piperidyl)-1-phenylindole (10.19 g).