Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CC2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)cc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-methoxybenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 28% yield: mp 116-118° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 5H), 7.08 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.00 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.29-4.20 (m, 1H), 3.97-3.88 (m, 1H), 3.76 (s, 3H), 3.37-3.27 (m, 1H), 2.82-2.67 (m, 2H), 2.63 (s, 3H), 2.08-1.93 (m, 1H), 1.92-1.71 (m, 2H), 1.62-1.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 156.7, 152.3, 151.1, 146.2, 131.9, 124.9, 124.2, 122.9, 121.9, 121.7, 113.4, 107.9, 49.3, 42.2, 38.3, 38.1, 30.7, 18.8, 15.3, 11.4; MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][N:11]([CH3:10])[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:8])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=C(Cl)CCCCCBr
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)C(=O)CCCCCBr)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 ml of 6-bromohexanoyl chloride were dissolved in a mixture of 100 ml of absolute dichloromethane and 100 ml of absolute toluene. A solution of 13.6 g of N-methyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-amine and 9.5 ml of triethylamine in 25 ml of absolute toluene was added dropwise to the solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 12 hours. In order to work it up, the precipitated salts were filtered out and washed with toluene. The filtrate was washed first with 1 molar citric acid solution and then with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. 19.3 g of 5-{N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminocarbonyl}-pentyl bromide were obtained as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[N:30]=2)[N:14]=1>CS(C)=O>[CH3:5][O:4][CH2:3][CH2:2][O:25][C:21]1[CH:20]=[C:19]([CH2:18][N:17]2[C:13]([CH3:12])=[N:14][C:15]([C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:39])([F:41])[F:40])=[CH:33][CH:32]=4)[N:30]=3)=[N:16]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COCCBr
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)cs3)nc2C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-bromo-2-methoxyethane (3.2 mg, 0.023 mmol), Cs2CO3 (9.4 mg, 0.029 mmol) and 3-((5-methyl-3-(4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (5.0 mg, 0.012 mmol; synthesized in analogous manner to Example 59, using 2-(5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole, Example 87, Step 4) in DMSO (0.2 ml) was stirred at 50° C. for 20 minutes. The mixture was purified by prep-HPLC to give the title compound; MS (ES+) C23H21F3N4O3S requires: 474. found: 475 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:14][OH:15]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=C1CCN(CCCCO)CC1
Agent: Cl
Product: OCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Hydroxybutyl)-4-piperidone oxime is prepared from 1-(4-hydroxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:25][OH:26])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:11][C:10]1=2.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:26][CH2:25][C@@:3]23[C@@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:17]=[N:16][C:15]4[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[N:11][C:10]2=4)[O:4]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:49]=[CH:50][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]c(NC(=O)C(C)C)nc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 51 (440 mg, 1.21 mmol) and 4,4′-dimethoxytrityl chloride (573 mg, 1.69 mmol) was dissolved in anhydrous pyridine (7 cm3) and was stirred at room temperature for 4 h. The mixture was evaporated under reduced pressure to give an oil. Extraction was performed in a system of dichloromethane/water (1:1, v/v, 40 cm3). The organic phase was separated and concentrated to give a solution in a minimal volume of dichloromethane containing 0.5% of pyridine (v/v) which was applied to a silica gel column equilibrated by the same solvent. The product was eluted in gradient concentrations of methanol (0.6-2%, v/v) in dichloromethane containing 0.5% of pyridine (v/v) to give compound 52 as a white solid material (695 mg, 86%). δH (CDCl3) 12.17 (1H, br s, NHCO), 10.09 (1H, br s, NH), 7.87 (1H, s, 8-H), 7.42-6.72 (13H, m, DMT), 5.69 (1H, s, 1′-H), 4.59 (1H, s, 2′-H), 4.50 (1H, s, 3′-H), 3.98 (1H, d, J 8.1, 1″-Ha), 3.69-3.39 (9H, m, DMT, 5′-H, 1″-Hb), 2.72 (1H, m, CHCO), 1.17 (6H, d, J 6.8, CH3CH). δC (CDCl3) 179.8 (COCH), 158.8, 144.5, 135.6, 135.5, 130.1, 128.1, 127.7, 126.9, 113.2 (DMT), 155.8, 147.9, 147.5, 137.0, 120.8 (guanine), 87.6, 86.4, 86.1 (C-1′, C-4′, DMT), 79.7 (C-3′), 72.6, 71.4 (C-2′, C-5′), 59.8 (C-1″), 55.2 (DMT), 36.1 (COCH), 19.1, 18.8 (CH3CH). FAB-MS m/z 668 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nc(-c2ccc(F)cc2)cs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccc(F)cc4)cs3)(CC1)CC2
Yield: 65.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(4-fluorophenyl)thiazole (66.1 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(4-fluorophenyl)thiazol-2-yl]amino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (50.6 mg).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([NH2:13])=[NH:12])[CH2:3]2.C[O-].[Na+].CN(C)[CH:19]=[CH:20][C:21]([C:23]1[N:30]2[C:26]([O:27][CH:28]=[CH:29]2)=[N:25][C:24]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=O>C(O)C>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:24]2[N:25]=[C:26]3[N:30]([C:23]=2[C:21]2[CH:20]=[CH:19][N:13]=[C:11]([NH:10][C@@H:4]4[CH:5]5[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]5)[CH2:3]4)[N:12]=2)[CH:29]=[CH:28][O:27]3)=[CH:36][CH:35]=1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Reactant: N=C(N)NC1CN2CCC1CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@H]3CN4CCC3CC4)n2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A 5 L 3-neck round bottom flask is charged with the N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride (261.5 g, 1.277 mol) and absolute ethanol. Sodium methoxide (21% by weight) (405 ml, 1.08 mol) is added dropwise over 15 min. The 3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one (232.1 g, 0.776 mol) is then added in portions so that no reaction mixture temperature change is observed. The reaction mixture is then refluxed for 5 hours and cooled to room temperature. Solvent is removed in vacuo and the residue partitioned between 1N NaOH and ethyl acetate. The resulting solids are filtered, washed with water, ethyl acetate, and then dried. The solids are then mostly dissolved in hot isopropyl alcohol and filtered through celite while hot. The isopropyl alcohol solution is concentrated to dryness and the solids dried under vacuum to give the desired pyrimidine compound (143.8 g) as a tan solid in 46% yield.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[C:10]([CH3:22])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2ccc(F)cc2)cn1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole (18.2 g, 59.2 mmol) was dissolved in 600 mL dry THF and cooled to −78° C. n-Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane (7.4 mL, 11.8 mmol) was added dropwise. The reaction mixture was slowly warmed up to room temperature and stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 50:50->20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%), MS: m/e=321.1 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C(C=O)C=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39].NCCCCN1C2C3C=CC=CC=3N=C(N)C=2N=C1COC.FC(F)(F)C([O-])=O>>[CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=Cc1ccccc1
Agent: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=C([O-])C(F)(F)F
Agent: O=Cc1cccnc1
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1ccccc1

Procedure:
The compounds in the table below were prepared and purified according to the methods of Parts B and C of Examples 467-478 using 1-(4-benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine. 1-(4-Benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the general method of Part A of Examples 467-478 using benzaldehyde in lieu of pyridine 3-carboxaldehyde and 1-(4-aminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 3-bromoindazole (500 mg, 2.54 mmol) in 8 ml CH2Cl2 was added triethyl amine (1.06 ml, 7.61 mmol) at room temperature. To this yellow solution was added 2-(trifluoromethyl)benzenesulfonyl chloride (0.392 ml, 2.54 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified on SiO2 using 5% to 20% ethyl acetate in heptane to give 3-bromo-1-(2-(trifluoromethyl)phenylsulfonyl)-1H-indazole (894 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40]O)=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:47]#[CH:48])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:47]#[CH:48])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2Oc2ccc(OCCO)cc2)N1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Oc2ccc(OCC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in Example 2, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.9 g, 1.26 mmol) was reacted with trimethylsilyl acetylene (0.25 g, 2.5 mmol), CuI (0.48 g, 2.5 mmol), triethylamine (0.25 g, 2.5 mmol) and dichlorobis(triphenylphosphine) palladium(0) (0.18 g, 0.025 mmol) in tetrahydrofuran, then treated with aqueous NaOH solution in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{5-ethynyl-2-[4-(2-ethoxy)-phenoxy]-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.58 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[OH:30])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[O:30][CH:47]([CH3:49])[CH3:48])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)N1CCN(C(CN2CCN(CCCCc3c(O)ccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2ccccc2c1CCCCN1CCN(CC(c2ccc(F)cc2)N2CCN(C(C)C)CC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
0.05 g of 1-[2-(4-Fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-hydroxynaphthalen-1-yl)butyl]piperazine obtained in Example 7 was dissolved in 5 ml of dimethylformamide, and 0.19 g of potassium carbonate and 0.068 ml of 2-iodopropane were added, followed by stirring at 70° C. for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.03 g of 1-[2-(4-fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-isopropoxynaphthalen-1-yl)butyl]piperazine as an oil.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][F:22])[C:15]([O:17][CH3:18])=[O:16]>CO>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][F:22])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=COCF)c1ccccc1OC1CCCCO1
Solvent: CO
Product: COC(=O)C(=COCF)c1ccccc1O
Yield: 72.9 %

Procedure:
6.2 g (0.02 mol) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-fluoromethoxy-acrylate are stirred in 30 ml of methanol at 20° C for 18 hours with 0.5 g of acidic ion exchanger. The ion exchanger is filtered off and the filtrate is concentrated. The residue is chromatographed on silica gel using hexane/acetone (7:3). 3.3 g (73% of theory) of methyl 2-(2-hydroxyphenyl)-3-fluoromethoxy-acrylate are obtained as a pale yellow, viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent 20 ml of dichlorometane and 20 ml of trifluoracetic acid was added and the mixture was stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then ethylacetate was added and the mixture was extracted two times with water. The aqueouos phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=9:1) to yield 2.1 g (65%) of (S)-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4] diazepin-2-one.
Reaction SMILES: [Cl:1][CH2:2][CH:3](O)[CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[CH2:11][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.C[OH:33]>>[ClH:1].[CH:24]1([NH:30][CH2:2][CH2:3][CH:4]([OH:33])[CH2:5][O:6][C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][O:14][C:9]=3[CH:8]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: CO
Reactant: OC(CCl)CCOc1ccc2c(c1)OCC(c1ccccc1)C2
Agent: Cl
Product: OC(CCNC1CCCCC1)COc1ccc2c(c1)OCC(c1ccccc1)C2
Reaction time: 3 h

Procedure:
A mixture of 6.64 g 1-chloro-4-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-butanol and 3.7 cm3 cyclohexylamine was kept at 95° C. for 3 hours. The mixture was dissolved in 10 cm3 of methanol, 6 cm3 of methanol saturated with hydrochloric acid was added thereto, then the solution was evaporated. The residue was dissolved in 40 cm3 of benzene, the benzene solution was extracted with water and evaporated; 6.2 g crude 4-cyclohexylamino-1-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-butanol-hydrochloride was obtained. The weight of the product crystallized from acetone is 5.0 g; melting point is 157°-159° C. The base liberated from its hydrochloric salt melts at 114°-116° C. The base can be transformed with methyl iodide into 1-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-4-(dimethyl-cyclohexylammonium)-2-butanol-iodide (m.p. is 208°).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([CH2:11]Cl)=[C:5]([Cl:13])[C:4]=1[Cl:14].C[O:16][P:17]([O:20][CH3:21])[O:18][CH3:19].CCl>C1(C)C=CC=CC=1>[CH3:19][O:18][P:17]([CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([CH2:11][P:17](=[O:16])([O:20][CH3:21])[O:18][CH3:19])=[C:5]([Cl:13])[C:4]=1[Cl:14])(=[O:16])[O:20][CH3:21]
Reactant: COP(OC)OC
Reactant: ClCc1c(Cl)c(Cl)c(CCl)c(Cl)c1Cl
Agent: CCl
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1c(Cl)c(Cl)c(CP(=O)(OC)OC)c(Cl)c1Cl)OC
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A mixture of α,α',2,3,5,6-hexachloro-p-xylene (6.26 g, 0.02 mol) in toluene (60 mL) and trimethylphosphite (7.0 mL, 7.4 g, 0.06 mol) is heated to reflux temperature. The flask is set up with a condenser, Dewi-Stark trap, and the nitrogen inlet positioned so that any methyl chloride produced in the reaction will be swept out the condenser. A clear solution resuites with heating and the solution is heated at reflux for 18 hours. The toluene is distilled from the flask via the Dean-Stark trap, more trimethylphosphite is added (7.0 mL), and the reaction is heated with an oil bath (~110° C.) for 48 hours. After standing at room temperature, a white solid formed in the flask. A TLC indicated that no starting material remained. Toluene (100 mL) is added to flask and the mixture is heated at reflux temperature with stirring until a clear solution is obtained. The reaction mixture is allowed to cool to room temperature and a white precipitate formed. The white solid is collected by filtration, washed with hexane, dried in a vacuum desiccator, to give 5.17 g of title compound, mp 179°-181° C. Recrystallization from ethyl acetate gives 2.44 g as white crystals, mp 181°-182° C. There are some problems keeping the product in solution during the filtration of the hot ethyl acetate solution so that a considerable amount of material crystallized out during filtration. These crystals are combined with the filtrate from the collection of the first crop and yielded 2.27 g. This material is recrystallized from ethyl acetate giving a second crop of 2.22 g, mp 181°-182° C.