Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]([C:37]3[S:41][C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=4)=[N:39][CH:38]=3)[CH:34]=[CH:35][CH:36]=2)=[CH:27]1.Cl.Cl[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH3:56]>C(Cl)Cl.CO>[CH2:53]([N:54]([CH2:57][CH3:58])[CH2:55][CH2:56][O:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]2[S:41][C:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)[CH:32]=3)=[CH:38][N:39]=2)=[CH:44][CH:45]=1)[CH3:52]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-[5-(3-thiophen-3-yl-phenyl)-thiazol-2-ylamino]-phenol and using (2-chloroethyl)-diethylamine hydrochloride. The title compound: ES-MS: 450.0 [M+H]+; single peak at tR=3.98 min (System 2); Rf=0.14 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][CH2:37][CH3:38])[N:30]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:36]([CH2:37][CH3:38])[CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][CH2:26][CH3:27])[N:30]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccc(NCC)n1
Product: CCNc1cccc(CN(CC)C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)n1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-yl)-amine
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11](OC)=[O:12])[N:8]=1)([O-:3])=[O:2].[NH3:17]>CO>[N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([NH2:17])=[O:12])[N:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: N
Solvent: CO
Product: NC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionate (5.00 g, 21.3 mmol), 10% ammonia solution (80 ml) in methanol was added and stirred for 3 hours at a room temperature. Then, the reaction mixture was concentrated. Methanol (100 ml) was added to the concentrate and throughly stirred. Insoluble fraction was filtered off. The filtrate was concentrated, subjected to silica gel column chromatography and recrystallized from ethanol to obtain 3-(2'-nitroimidazolyl)-2,2-difluoropropionic acid amide (2.57 mg). m.p. 149.5°-151.5° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH:20]=O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH2:20][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(F)cc(OC)cc1F
Yield: 55 %

Procedure:
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. 2,6-Difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) was added, and the mixture was stirred while elevating the temperature to room temperature for 4 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:10-1:5), and then subjected to catalytic reduction in the same manner as in Reference Example 172 to give the title compound (1.17 g) as a colorless oil. yield 52%. MS 245.0 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(=O)(O)[O-].[Na+].[C-:18]#[N:19].[Na+].[CH2:21]([NH:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CO>[CH2:21]([N:28]([CH:7]([C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)[C:18]#[N:19])[CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCNCc1ccccc1
Reactant: [C-]#N
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(c1ccc(C(F)(F)F)cc1)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
4-(Trifluoromethyl)benzaldehyde (CAS #455-19-6, 2 g) and methanol (1 mL) were added to a solution of sodium bisulfite (1.33 g) in water (40 mL) at room temperature, and the mixture was stirred at room temperature for 10 minutes. Sodium cyanide (1.33 g) was added to the reaction solution, and the mixture was stirred at the same temperature for 40 minutes. N-Benzylethanolamine (1.83 g) and methanol (3 mL) were added to the reaction solution, and the mixture was stirred at the same temperature for 16 hours. The reaction solution was partitioned with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent:heptane:ethyl acetate=9:1→1:1) to obtain 1.79 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=O)C>C(N(CC)CC)C.CO.O>[C@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3ccc(O)cc3)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 49.6 %

Procedure:
A solution of 4.0 g of 4-hydroxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 53 ml of a mixture of 2N triethylamine:methanol:water (3:6:2) was stirred for 4 hours, chilled overnight and then concentrated to an oil. This oil was dissolved in water, extracted with three 500 ml portions of ether and both the water and ether layers were concentrated and combined. The combined concentrate was dissolved in 200 ml of water, acidified to pH 4 and chromatographed on Amberlite® XAD-2 resin, eluting with 500 ml of water, then 500 ml of methanol. The methanol extract was concentrated, giving 1.2 g of the desired intermediate [α]D26 =+31°±1° (1.144%, methanol).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([OH:8])[CH:5]([OH:7])[CH3:6].[CH3:9][OH:10].CO>C1(=O)OC(C)CO1>[CH2:4]([OH:8])[CH:5]([OH:7])[CH3:6].[C:4](=[O:8])([O:10][CH3:9])[O:2][CH3:1]
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: CC1COC(=O)O1
Solvent: CC(O)CO
Product: COC(=O)OC

Procedure:
In a process as described in FIG. 1 7 t/h (tonnes per hour) propylene carbonate is fed into the upper part of a reactive distillation zone. Sodium methanolate in 0.5 t/h propylene glycol/methanol mixture as transesterification catalyst is also passed into the upper part of zone in an amount of 0.05 t/h. Twenty t/h methanol, fed into a lower part of the distillation zone, passes upward, and reacts with the propylene carbonate to form propylene glycol product and dimethyl carbonate. The propylene glycol is recovered in an amount of 5 t/h.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: OCCN1CCN(c2cncc(Cl)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2 mmol, 1 eq) and 2-(4-(6-chloropyrazin-2-yl)piperazin-1-yl)ethanol (57) (49.5 mg, 0.2 mmol, 1 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.4 mmol, 2 eq) followed by addition of Pd(PPh3)4 (1.0 mg, 0.04 mmol) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 3% MeOH/CHCl3 to obtain pale yellow solid compound 2-(4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-1-yl)ethanol 126 in 15 mg quantity. The compound 126 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 8.96 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.36 (m, J=289.99, 1H), 6.61 (m, J=301.8, 1H), 3.75 (m, J=5.0, 6H), 2.69 (m, J=4.84, 6H); MS m/z 324.9 (M+H)+.
Reaction SMILES: C[C:2]12[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.C([OH:13])C>[Pd]>[CH2:8]1[CH:7]2[CH:2]([CH:3]([OH:13])[CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:9]1
Reactant: CCO
Reactant: CC12CCCCC1CCC2
Agent: [Pd]
Product: OC1CCCC2CCCC12
Reaction time: 12 h
Yield: 100 %

Procedure:
Typically, the compound of formula VI, (1R,3aR,4S,7aR)-4-Hydroxy-1-[(S)-3-[2-(carboxylic acid ethyl ester)-phenyl-1-methyl-propynyl]-7a-methyl-octahydro-indene (218 mg; 0.615 mmol) was dissolved in dry ethanol (12 ml). Palladium on carbon (10%; 55 mg) was added and the reaction was put under hydrogen at one atmosphere for 12 hours at room temperature. The catalyst was filtered off and the solvent was evaporated. The compound of formula VI of the above Example 1E, the [1R,3aR,4S,7aR]-7a-Methyl-1-[(S)-1-methyl-3-[2-(carboxylic acid ethyl ester)-phenyl-propenyl]-octahydro-inden-4-ol (226 mg; yield: 100%) was obtained as a yellowish oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:20][C:21]1([F:67])[CH2:26][CH2:25][CH:24]([C:27]2[C:36]3[CH:35]([O:37]CC4C=CC(OC)=CC=4)[CH2:34][C:33]([CH3:48])([CH3:47])[CH2:32][C:31]=3[N:30]=[C:29]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[C:28]=2[CH:55]([F:66])[C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)[CH2:23][CH2:22]1>>[F:67][C:21]1([F:20])[CH2:26][CH2:25][CH:24]([C:27]2[C:36]3[CH:35]([OH:37])[CH2:34][C:33]([CH3:47])([CH3:48])[CH2:32][C:31]=3[N:30]=[C:29]([CH:49]3[CH2:54][CH2:53][N:52]([C:2]4[N:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=4)[CH2:51][CH2:50]3)[C:28]=2[CH:55]([F:66])[C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:64])([F:65])[F:63])=[CH:58][CH:57]=2)[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Clc1ncc(Br)cn1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(S(C)(=O)=O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(methylsulfonyl)pyrimidine, which was prepared by a method similar to that of Reference Example 14, instead of 5-bromo-2-chloropyrimidine, and from 49 mg (72 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 45 mg of the title compound was obtained as a white solid (yield: 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[C:4]([CH3:21])([CH3:20])[O:3]1.CNN>ClCCl>[CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][O:8][NH2:9])[C:4]([CH3:21])([CH3:20])[O:3]1
Reactant: CC1(C)OC(CON2C(=O)c3ccccc3C2=O)C(C)(C)O1
Agent: CNN
Solvent: ClCCl
Product: CC1(C)OC(CON)C(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
2-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (0.158 g, 0.52 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C., and charged with methylhydrazine (30 μL, 0.57 mmol). The ice bath was removed and the reaction was allowed to stir at ambient temperature for 1 hour. The reaction mixture was diluted with diethylether and the solids were filtered off and filtrate concentrated in vacuo to afford O-(2,2,5,5-tetramethyl-[1,3]dioxolan4-ylmethyl)-hydroxylamine as a yellow oil (0.042 g, 46%). 1H NMR (400 MHz; DMSO-d6) δ 6.06 (bs, 2H), 3.84-3.87 (m, 1H), 3.50-3.59 (m, 2H), 1.26 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 0.94 (s, 3H); MS (APCI+)=176.9.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:5][CH2:4]1
Reactant: CON1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
21 g 1-Methoxy-piperidin-4-ol (from Step 1) and 19.4 g triethylamine were dissolved in 200 ml ethyl acetate, and cooled to 0° C. 15.0 g Methanesulfonyl chloride was added slowly. The resulting white suspension was stirred at 0° C. for 1 hour, then at room temperature for an additional 1 hour. Then the mixture was filtered and the solvent evaporated, yielding 34.6 g of methanesulfonic acid 1-methoxy-piperidin-4-yl ester. This material was used for the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:2][N:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
The title compound is prepared as described in Example 1 for 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine but using 1-chloro-2-dimethylaminoethane hydrochloride. Title compound: ES-MS: 181.2 [M+H]+; Rf=0.18 (CH2Cl2/MeOH, 70/30).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([OH:11])[CH:7]=[CH:6][CH:5]=2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:16][C@H:17]1[O:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:19]1[CH2:18][C@H:17]1[CH2:16][O:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:2]([CH3:1])[NH:3]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Yield: 50.7 %

Procedure:
Prepared from 2-methyl-4-hydroxyindole (5 g, 33 mmol), (S)-glycidyl nosylate (8.78 g, 33 mmol) and potassium carbonate (4.56 g, 33 mmol) according to the procedure used for Intermediate 1 to give 3.4 g product as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccccc1C1=CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Product: O=Cc1ccccc1C1CCCCC1
Yield: 65 %

Procedure:
16.3 g. (0.1 mol) o-(1-Cyclohexenyl)-benzaldehyde were heated for 4 hours in a Dean and Stark apparatus with 6.85 g. (0.11 mol) ethyleneglycol and 1 g. p-toluenesulphonic acid in 400 ml. toluene. Thereafter, the calculated amount of water had separated off. The isolated protected aldehyde was taken up in ethanol and hydrogenated over platinum oxide as catalyst. After filtering and evaporating off the solvent, the crude product was taken up in 300 ml. dioxan, mixed with 80 ml. of a 10% aqueous solution of oxalic acid and heated under reflux for 2 hours. After extraction with ethyl acetate, the organic phase was washed with water, dried over anhydrous magnesium sulphate and evaporated. Flash chromatography (hexane/ethyl acetate 5:1 v/v) gave the aldehyde in pure form in a yield of 65% of theory.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:29][C:30]1[CH:31]=[C:32]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Yield: 79.3 %

Procedure:
2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.80 g, 22.78 mmol) and 1,3-dibromobenzene (21.49 g, 91 mmol) were dissolved in toluene (300 mL), and potassium carbonate (9.44 g, 68.3 mmol) in 50 mL of water and the Pd(PPh3)4 catalyst (0.263 g, 0.228 mmol) were then added. The reaction mixture was degassed and refluxed under N2 overnight. The organic layer was then separated, evaporated and subjected to column chromatography on silica gel, eluted with hexane/DCM 9:1 v/v mixture, providing 4-(3′-bromo-[1,1′-biphenyl]-3-yl)dibenzo[b,d]thiophene (7.5 g, 18.06 mmol, 79% yield) as white solid.
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C1(O[C:20]#[N:21])C=CC=CC=1.[OH-].[Na+]>C1COCC1.CCCCCC>[CH:1]1([C:6]#[C:7][C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#COc1ccccc1
Reactant: C#CC1CCCC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC#CC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (2.23 mL). The mixture was stirred for 15 min followed by the dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was warmed to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford product (600 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[CH2:15][CH3:16].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1.C(O)C>[CH2:15]([C:5]1[N:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:16]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 98.9 %

Procedure:
3-(2-chloroethyl)-2-ethylquinazoline-4(3H)-one (1.5 g; 6.34 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine (1.459 g; 6.34 mmol), sodium carbonate (0.672 g; 6.34 mmol), sodium iodide (0.95 g; 6.34 mmol), ethanol (100 mL) and toluene (200 mL) were added to a 100 mL reactor. The reaction medium was heated to reflux and kept under agitation for a period of 24 hours, during which 250 mL of solvent were slowly removed with assistance from a Dean Stark. The reaction was monitored through CG/MS until completion. After the end of the reaction, ethyl acetate (250 mL) was added, together with an aqueous solution of acetic acid (100 mL; 10%). The mixture was maintained under agitation for a period of 30 minutes. The organic phase was separated, washed with two portions of 50 mL of NaHCO3 at 5%, dried with MgSO4 and evaporated at reduced pressure, yielding a pale yellow colored oil (2.7 g of raw 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4(3H)-one). This oil was dissolved in isopropanol, adding 2.0 mL of concentrated HCl to the resulting solution. The solution was kept under agitation at room temperature, until completing precipitation of the solids. The solids were vacuum filtered, washed with two portions of 5 mL of isopropanol and dried, yielding 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4(3H)-one hydrochloride as a pale white solid (2.36 g, 5.48 mmol, yield: 87%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:24])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][CH:10]=[O:24]
Reactant: CC1CC(C)(C)CC1CC#N
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C)(C)CC1CC=O
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acetonitrile 4 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.