Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:21])[CH:13]=[CH:12][C:11]=2[NH:14][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Yield: 100.3 %

Procedure:
A solution of 365 mg (1.18 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 827 mg (1.78 mmol) of PyBroP, 398 mg (1.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 618 μL (3.55 mmol) of DIEA at RT for 16.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-40% EtOAc-hexane afforded 660 mg (100%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C27H39N5O4SSi, 558.2 (M+H). found 557.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.C([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)C1C=CC=CC=1>C1COCC1>[OH:28][C:25]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCNCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 15 g of 2-bromoanisole in 50 ml of THF is cooled to -70° C., under nitrogen, a 1.6M solution of n-butyllithium in THF is added dropwise and the mixture is kept stirring for 1 hour. The mixture is cooled to -70° C. and a solution of 15.2 g of 1-benzylpiperid-4-one in 50 ml of THF is added dropwise. The mixture is kept stirring while allowing the temperature to rise to RT and after 1 hour, the reaction mixture is concentrated under vacuum. The residue is taken up in AcOEt, the organic phase washed with water, with a saturated solution of NaCl, dried over MgSO4 and the solvent evaporated under vacuum. 14 g of the expected product are obtained after crystallization from the AcOEt/ether/heptane mixture.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18]N1C(=O)CCC1=O.CCOC(C)=O.C1CCCCC1>CC#N>[Cl:18][C:10]1[C:11]([NH2:15])=[CH:12][N:13]=[N:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Nc1cnnc(-c2cccc(C(F)(F)F)c2)c1Cl
Yield: 52.1 %

Procedure:
6-[3-(Trifluoromethyl)phenyl]-4-pyridazinamine (2.0 g, 0.0084 mole, Compound No. 4) and N-chlorosuccinimide (0.61 g, 0.004 mole) were refluxed under N2 in CH3CN (50 mL) for 1.5 h. After this time no starting material was present by TLC. The mixture was partitioned between EtOAc/water. The organic layer was extracted again with water, dried (MgSO4), filtered and evaporated to give a crude oil. The oil was chromatographed on a Prep-500 using EtOAc/cyclohexane (9:1) to give a crude solid. The solid was recrystal-lized from EtOAc/cyclohexane to give 5-chloro-6-[3-(trifluoromethyl)phenyl]-4-pyridazinamine (0.57 g, 50% yield, Compound No. 35) as a tan solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:27][C:28]#[N:29])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
A suspension of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 52 mg, 0.20 mmol), potassium carbonate (43 mg, 0.31 mmol), bromoacetonitrile (15 μL, 0.22 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred at 60° C. for 2.5 hours. After cooling to room temperature, water (10 mL) was added thereto and the precipitated solid was filtered off. The obtained solid was dried under reduced pressure to give the target compound (32 mg) as a pale brown solid (Yield 54%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>C1COCC1>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccsc1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
To a solution of 2-aminothiophene-3-carboxamide (800 mg, 5.63 mmol, 1.0 eq.) in THF (15 mL) and Et3N (626 mg, 6.19 mmol, 1.1 eq.) was added nicotinoyl chloride (795 mg, 5.63 mmol, 1.0 eq.) in anhydrous THF (15 mL) dropwise. The resulted mixture was stirred at room temperature overnight. After the reaction was completed, the volatiles were evaporated. The residue was washed with CH2Cl2 (20 mL). The resulting solid was collected and dried in vacuo to give 1.50 g of N-(3-carbamoylthiophen-2-yl)nicotinamide as a brown solid (quantitative yield). LCMS m/z=248.1 (M+1) (Method B) (retention time=1.34 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(#N)C.[I-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([O:17][C:11]2[C:10]([Cl:9])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:16])[N:3]=[CH:4][N:5]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc(Oc2c(Cl)cccc2Cl)ncn1
Yield: 70.8 %

Procedure:
4,6-Dichloropyrimidine (149 mg, 1.0 mmol), 2,6-dichlorophenol (179 mg, 1.1 mmol), potassium carbonate (166 mg, 1.2 mmol), and sodium iodide (7.5 mg, 0.05 mmol) were stirred in acetonitrile (3 mL) at 20° C. under an atmosphere of nitrogen for 64 h. The reaction was poured onto 1N aqueous sodium hydroxide solution and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound (195 mg, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>C1COCC1.CO.[Ni]>[NH2:21][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13]1
Reactant: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1

Procedure:
30 g of 6-benzyloxy-2,2-dimethylchroman-4-one oxime were dissolved in 900 ml of THF/methanol (1:1), treated with 25 ml of aqueous ammonia and hydrogenated in a shaking duck with Raney Ni. The catalyst was then filtered off with suction, the filtrate was concentrated in vac., the residue was dissolved in EA, the solution was dried and concentrated, and the residue was crystallized using petroleum ether, 22.9 g , m.p. 86-88° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4]C(O)C.[OH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][CH2:3][CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(O)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 134.4 %

Procedure:
104.9 g (842.5 mmol) 2-chloroethoxyethanol, 500 ml dimethylformamide (DMF), 70 g (421.2 mmol) ethyl 4-hydroxybenzoate, and 116.3 g (842.5 mmol) potassium carbonate were introduced into a flask in a nitrogen stream and stirred at 80° C. for 17 hours. The insolubles were filtered off, and the filtrate was concentrated, then introduced into a saline solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate anhydride, and the solution was concentrated to give 119 g crude ethyl 4-(2-hydroxyethoxy)benzoate. Subsequently, 150 ml ethanol and 200 ml aqueous solution of 33.7 g sodium hydroxide were added thereto, and the mixture was stirred at 70° C. for 2 hours. After the reaction solution was left and cooled, 72 ml conc. hydrochloric acid was added thereto on an iced bath, and the precipitates were filtered, and washed with water to give 89 g (76.2 mmol) 4-(5-hydroxy-3-oxapentyloxy) benzoic acid (compound (XIII) [R9, R10, R11, R12=H; X1=—(CH2CH2O)2—] in scheme (3)). Then, 800 ml toluene, 76.5 g (1060 mmol) acrylic acid and 10.1 g(53mmol)p-toluenesulfonicacidmonohydrate(referred to hereinafter as “PTSA”) were added thereto, and the mixture was esterified for 3 hours in a Dean-Stark tube. The insolubles were filtered, and washed with toluene, then suspended in water, filtered and dried to give 86 g of the desired product. The yield was 78%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.O>CN(C)C=O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[CH:20]=[CH:19][CH:18]=[C:17]3[C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: Cc1ccc(-n2cccc2)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(c1)C(=O)c1cccn1-2
Temperature: 25 °C
Yield: 35 %

Procedure:
At 0° C., add 1.36 ml (14.9 mmol) of phosphorus oxychloride to 1.14 ml (14.9 mmol) of dimethylformamide, then add a solution of 3 g (14.9 mmol) of 5-methyl-2-pyrrol-1-ylbenzoic acid (Preparation 25) in 30 ml of dimethylformamide. After one night's stirring at room temperature, hydrolyse the reaction mixture by pouring into 50 ml of water, extract with 200 ml of diethyl ether, and wash the ethereal phase in succession with water, a saturated aqueous hydrogen carbonate solution and then water. After drying over magnesium sulfate and rendering colourless with animal charcoal, the ethereal phase is concentrated to dryness to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:32](Cl)=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=2)=[O:30])=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][C:36]1[C:31]([C:29](=[O:30])[NH:28][C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)=[CH:32][N:33]=[C:34]([S:37][CH3:38])[N:35]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (0.500 g, 3.12 mmol) and DIPEA (0.83 mL, 4.68 mmol, 1.5 eq) was added to a solution of 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (0.929 g, 3.12 mmol) in DMF (5.0 ml) and stirred under N2 overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed twice with water (50 mL). Upon precipitation of product out of the organic layer of the mixture, the white solid was filtered, and recrystallized from hot ethyl acetate to yield 1.06 g (80%) of the titled product as a white solid. 1H NMR: (d6-DMSO) δ 10.21 (s, 1H), 8.56 (s, 1H), 7.64 (m, 2H), 7.16 (m, 2H), 6.92 (t, 1H), 3.48 (m, 2H), 3.30 (s, 3H), 3.11 (m, 2H), 1.31 (s, 9H); HPLC: Rt=4.32 min; MS (ESI): m/z 419.97 (M−H)−.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:16].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:38]1[CH2:39][CH2:40][CH:35]([C:31]2[CH:30]=[C:29]([NH:28][C:26](=[O:27])[CH:25]([CH3:24])[CH3:41])[CH:34]=[CH:33][CH:32]=2)[CH2:36][CH2:37]1
Reactant: O=C(CCCCCCl)c1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 6-chloro-1-(2-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 439.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:37]([CH3:39])[CH3:38])/[CH:26]=[C:27](/[P:29]([O:34]CC)([O:31]CC)=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[Si](Br)(C)C>C(Cl)Cl>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:37]([CH3:39])[CH3:38])/[CH:26]=[C:27](/[P:29]([OH:31])([OH:34])=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOP(=O)(OCC)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)P(=O)(O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.5 %

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-(diethoxyphosphoryl)-1-isopropyl-but-2-enyl]-N1,3-dimethyl-L-valinamide (11 mg, 0.02 mmol, from Example 71) in CH2Cl2 (0.5 mL) is treated with TMSBr (23 mg, 0.15 mmol). The reaction mixture is stirred at room temperature for 20 h, then concentrated. The residue is purified by reversal phase HPLC (mobile phase A: 0.02% TFA/H2O, mobile phase B: 0.02% TFA/CH3CN) to give 2.4 mg (19%) of desired product as a white solid. HRMS (ESI) calcd for C26H44N3O5P [M+H] 510.3091, found 510.3086.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[C:5]2[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:4]=12)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:5]=23)=[O:20])[CH:16]=[C:15]([CH3:17])[C:14]=1[O:18][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)c2c1CC(C)(C)CC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (75 mg, 0.20 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (75 mg, 0.60 mmol) and the mixture is stirred at rt for 1 h. The mixture is diluted with acetonitrile (1 mL) and separated by prep. HPLC (Phenomenex Aqua, 75×30 mm ID, 10 μm, 10-95% acetonitrile in water containing 0.5% formic acid) to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (50 mg) as a colourless resin; LC-MS: tR=1.21 min, [M+1]=427.41.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)=[N+]=[N-].O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
111.6 mg (0.50 mmol) of 4-azidobenzophenone (5), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction product, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 87.7 mg (0.45 mmol) of 4-aminobenzophenone (6). The yield was 89%. The reaction is expressed by the following scheme.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:16])[NH:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)(F)c1ccncc1Br
Reactant: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1c1cnccc1C(F)(F)F
Yield: 3.9 %

Procedure:
3-Methyl-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-43d: 60 mg, 0.26 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (88 mg, 0.39 mmol), 1,4-dioxane (5 mL), copper iodide (14 mg, 0.078 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (3.7 mg, 0.026 mmol) and potassium phosphate (166 mg, 1.78 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3), followed by preparative HPLC afforded 3.8 mg of the product (3.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[O:5])[CH3:2].[C:12]12([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:12]23[CH2:13][CH:14]4[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]4)[CH2:21]2)[CH2:19]3)=[CH:27][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCCl
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CCOC(=O)CCCCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the procedure describe in Example 5, the use of 5-chloro-pentanecarboxylic acid ethyl ester and p-(1-adamantyl)-phenol as starting materials gives 5-[4-(1-adamantyl)-phenoxy]-pentanecarboxylic acid ethyl ester of boiling point 170°-180° C (0.05 mm).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:35])[C:13]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([OH:27])[CH2:14][C:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[O:25]C)([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[CH2:4][O:3]1.B(Br)(Br)Br>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:35])[C:13]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([OH:27])[CH2:14][C:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[OH:25])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[CH2:4][O:3]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccc1)C(=O)Nc1ccc2c(c1)COC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CC(O)(Cc1ccccc1)C(=O)Nc1ccc2c(c1)COC2=O)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-benzyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide (25 mg, 0.053 mmol) in anhydrous methylene chloride (1 mL) and cooled in ice was added boron tribromide (0.3 mL of 1 M solution in methylene chloride, 0.3 mmol). The reaction was stirred at room temperature for 3 hours and then quenched with water (5 mL). Methylene chloride (25 mL) was added, the organic layer separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give a light brown oil which was purified by preparative TLC eluting with methylene chloride-EtOAc (9:1) to give the title compound as a light, cream colored solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:26](=[O:27])[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]4[N:46]=[CH:47][N:48]=[C:22]34)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCCC1>[C].[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:26](=[O:27])[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]4[N:46]=[CH:47][N:48]=[C:22]34)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(c3ccc(OCc4ccccc4)cc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(c3ccc(O)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(4-{1-[4-(benzyloxy)phenyl]piperidin-4-yl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (364 mg), 10% palladium-carbon (containing water by 50%, 91 mg), tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at room temperature for 16 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by preparative HPLC [eluent: 0.1% trifluoroacetic acid-containing acetonitrile/0.1% trifluoroacetic acid-containing water=5/95→100/0 (volume ratio)] to give the title compound as a colorless amorphous compound (183 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11].[H][H]>C1COCC1.[Ni].CCO>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCN=C(NCCC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN=C(NCCC)c1cc(Cl)ccc1N

Procedure:
27.4 g (0.097 mol) of 5-chloro-2-nitro-N,N′-dipropylbenzamidine are dissolved in 200 ml of THF and are hydrogenated in the presence of 15 g Ra—Ni/EtOH at room temperature for 5 hours (take up of hydrogen: 94%). Then the catalyst is filtered off and the solvent removed in a water jet vacuum. The residue is purified by column chromatography on silica gel (eluant: hexane/THF 1:1, then THF). Yield: 11.9 g of 2-amino-5-chloro-N,N′-dipropylbenzamidine in the form of a brown oil (1H-NMR (CDCl3);.ppm/multiplicity/number of H's): 0.91/m/6H; 1.56/m/4H; 3.10/m (broad)/4H, 3.75/s(broad)/2H; 6.63/d/1H; 7.02/d/1H; 7.10/dd/1H.