Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC2C=CC(OC)=CC=2)=[O:25])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C/C(=C\CCCCCC)/C(C1C2C(=CC=CC=2)N(CCCC(OCC2C=CC(OC)=CC=2)=O)C=1)=O>>[CH2:36]([CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=1)=[O:11])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC(=CC(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)CCCCCCC
Agent: CCCCCC/C=C(\C)C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Product: CCCCCCCC(CCCCCCC)CC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 52 was repeated except that 4-methoxybenzyl 4-[3-(3-heptyl-2-decenoyl)-1-indolyl]butyrate obtained in Ex. 53 was used in place of (E)-4-methoxybenzyl 4-[3-(2-methyl-2-nonenoyl)-1-indolyl]butyrate to give 4-[3-(3-heptyldecanoyl)-1-indolyl]butyric acid as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)(=[O:27])=[O:26])=[CH:29][N:30]=2)[CH2:38][CH2:37]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccn1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccn3)s2)CC1
Yield: 90 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 90%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)[Cl:15]>>[CH2:1]([Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCCl
Temperature: 165 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
Into a reactor system in accordance with FIG. 1 there were pumped jointly per hour 1.65 kg lauryl alcohol (purity: 97%) and 0.41 kg phosphorus trichloride. The cooling was performed in reaction zone 1 in such a way that the outlet temperature was about 110° C. The residence time in reaction zone 1 was 5 minutes. Following preheating to 150° C for 2.5 minutes, the reaction mixture reached reaction zone 2 in which the reaction temperature was maintained with superheated steam at 165° C. The residence time in reaction zone 2 was 26 minutes. By means of a pressure maintenance valve, the entire reactor system was under a pressure of 30 atm. The product obtained in this manner separated out immediately into two phases. One obtained per hour 1.8 kg of the organic phase corresponding to a yield of 97.5% of lauryl chloride with respect to lauryl alcohol. The purity amounted to 95 weight-percent of lauryl chloride. The product contained 0.14 weight-percent of dilauryl ether. Space-time yield: 1.4 kg/hour, liter.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.[O:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH2:58][NH2:59]>>[O:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH2:58][NH:59][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: NCc1nc2ccccc2o1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2o1
Yield: 85 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[d]oxazol-2-ylmethanamine hydrochloride, the title compound was obtained as an off-white solid in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.74-7.68 (m, 1H), 7.56-7.49 (m, 1H), 7.40-7.24 (m, 4H), 7.09-6.99 (m, 2H), 6.50 (t, J=4.6 Hz, 1H), 6.14 (s, 1H), 4.88 (d, J=4.6 Hz, 2H), 4.44 (s, 2H), 3.85-3.76 (m, 2H), 3.49-3.39 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 465.2 (M+1), 487.2 (M+23).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=[O:29])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OC3CCOCC3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylate (7.3 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (32 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture, 1N hydrochloric acid (32 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from ethyl acetate-diethyl ether to give the title compound (5.9 g, yield 86%) as yellow powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][C:37]=1[O:51][CH3:52])=[O:34])[N:27]2[CH3:32]>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]3[N:3]=[C:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]4)[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=34)=[CH:38][C:37]=1[O:51][CH3:52])=[O:34])[N:27]2[CH3:32]
Reactant: CNC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Product: CNC[C@H]1CC[C@H](c2nc(-c3ccc(NC(=O)c4cc5c(OC)cccc5n4C)c(OC)c3)c3c(C)nccn32)CC1

Procedure:
Reaction of the impure 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-methylmethanamine (20 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (26 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol (containing 0.1% ammonium hydroxide)) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-((methylamino)methyl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (5.6 mg)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16](=[CH2:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2]>CCOC(C)=O.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:5][C:4]=1[C:22]([F:23])([F:25])[F:24])#[N:2]
Reactant: C=C(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A suspension of 5% Pd/C (0.060 g) in EtOAc (3 mL) was stirred under an H2 atmosphere (balloon pressure) for 15 min. A solution of methyl 2-{[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]methyl}acrylate (0.090 g, 0.245 mmol) in EtOAc (3 mL) was added and the mixture stirred for 1 hr. The catalyst was filtered off and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to afford 0.056 g (62% yield) of the title compound: MS (ES) m/z 369 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][OH:16].[OH-].[K+]>CN(C)C=O>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][O:16][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CCOCc1cccc([N+](=O)[O-])c1

Procedure:
158.1 g (0.92 mol) of 3-nitrobenzyl chloride was dissolved in a mixture of 500 ml (4.59 mol, 5 equivalents) of 3-methyl-1-butanol and 140 ml of dimethylformamide. To the resultant mixture 78 g (1.39 mol, 1.5 equivalents) of KOH pellets were added while the mixture was being cooled in a water bath and stirred strongly. The reaction temperature was elevated to 43° C. and thereafter gradually restored to room temperature. After the mixture was stirred for 7 hours at room temperature, the reaction was completed.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].O1CCCC1>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(c1nc2scnc2c(=O)n1Cc1ccccc1)N(CCN(C)C)Cc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
A solution of 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}-propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (14, 1 equiv) and 4-bromobenzaldehyde (2 equiv) in methanol is treated with a solution of sodium cyanoborohydride in tetrahydrofuran (1M, 2 equiv). Acetic acid is added to obtain a pH of 6-7 and the reaction is warmed at 60° C. for 18 h. An additional 2 equivalents of 4-bromobenzaldehyde and sodium cyanoborohydride are added after 18, 42 and 66 hours while maintaining the pH at 6-7 with acetic acid. After warming 90 h at 60° C., the reaction is concentrated and the residue is partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer is washed with brine, dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with EtOAc to 5% NH3-EtOH/EtOAC gives 6-benzyl-5-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)[1,3]thiazolo[5,4-d]pyrirnidin-7(6H)-one (2-1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:8].[C:23](Cl)(=[O:25])[CH3:24]>O1CCCC1.C(Cl)(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]2)[S:5][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: Nc1nc(NC2CCNCC2)sc1C(=O)c1cccc(F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluorophenyl)methanone (0.10 g, 0.31 mmol) (Example 6) was dissolved in a mixture of tetrahydrofuran (20 mL), chloroform (6 mL), and pyridine and cooled to −10° C. This was treated with acetyl chloride (0.032 g, 43 mmol) and stirred for 0.5 hr. at room temperature. This was diluted with cold methylene chloride (100 mL) and washed with 10% Na2CO3(aq) (2×). After drying (Na2SO4) and solvent removal, the residue was precipitated from a mixture of tetrahydrofuran and hexane to give 35 mg (30% yield) of 1-[4-[4-amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidin-1-yl]ethanone. 1H NMR (DMSO−d6, 300 MHz) δ1.28 (m, 1H, CH), 1.41 (m, 1H, CH) 1.92 (m, 2H, CH2), 2.75 (t, 1H, NCH), 3.14 (t, H, NCH), 3.32 (s, 3H, COCH3), 3.6-4.0 (broad, 1H, CH), 3.77 (d, 1H, NCH), 4.22 (d, 1H, NCH), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.72 (brd, 1H, NH). HRMS: (M+H)+: observed: 363.1288; calcd for 363.1286.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CO.C(Cl)Cl>CN(C=O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([NH:1][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(N)noc2c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 3-amino-6-methoxy-1,2-benzisoxazole (5.5 g) in N,N-dimethylfonamide (DMF) (100 ml) was added sodium hydride (1.2 g) under nitrogen. The reaction was stirred one hour at ambient temperature. A solution of 4-(2-chloroethyl)morpholine (5.4 g) in DMF (50 ml) was added to the reaction and heated to 125° C. for one hour. TLC (5% MeOH/DCM) revealed the absence of starting material. The reaction was quenched with water (1 l) and extracted with EtOAc (2 l). The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 3-4% MeOH/DCM afforded the product (4.5 g), m.p. 85°-86° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[S:38]([CH3:37])(=[O:40])=[O:39])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
347 mm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 433 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 30 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding thereto a solution of 46.4 mm3 of methylsulfonyl chloride in 5 mm3 of dichloromethane, and then it is stirred at room temperature for 1 hour. The reaction mixture is diluted with 20 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in methanol on a Bond Elut® SCX cartridge (10 g), eluting successively with methanol and with a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.44 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-methylsulfonamide is thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.81 (s:3H); 3.02 (broad t, J=7.5 Hz: 2H); 3.38 (broad t, J=7.5 Hz:2H); 4.23 (s:1H); 4.40 (mt:1H); 4.54 (s:2H); 6.75 (tt, J=9 and 2 Hz:1H); 6.95 (mt:2H); 7.25 (mt:8H)].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichlorophenyl)-6-trifluoromethyl-pyrimidine (example E.39) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.022 g, 10%). MS (ISP) 451.1 [(M+H)+]; mp 282.5° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][OH:13])[CH:6]=[C:5]2[CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([CH2:12][OH:13])[CH:6]=[C:5]4[CH3:14])=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(CO)nc2ccc(I)cc12
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cc1cc(CO)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
The product was obtained analogously to Example 7.1 e starting from (6-iodo-4-methylquinolin-2-yl)methanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 50 mg (19% of theoretical); C24H17ClN2O (M=384.857); calc.: molpeak (M+H)+: 385/387 (Cl); found: molpeak (M+H)+: 385/387 (Cl); HPLC-MS: 5.50 minutes (method B).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2,3-dichlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 25, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: O1CCCCC1[C:7]1([S:37][C@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH2:11]([O:10][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[S:37][CH:7]1[OH:8])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1(C2CCCCO2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OC1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A mixture of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (3.30 g, 5.15 mmoL), pyridinium p-toluenesulfonate (518 mg, 2.06 mmoL) and ethanol (58 mL) was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was concentrated. The resulting residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the titled compound (2.89 g, quant.) as a colorless crystal.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: BrCCCCCOc1cccc2c1CCCC2
Yield: 74.8 %

Procedure:
The title compound was prepared according to the procedure of Example 7 using 5,6,7,8-tetrahydronaphthalen-1-ol (8 g, 0.054 mol) in methylene chloride (100 ml), sodium hydroxide (4.32 g. 0.108 mol) in water (100 ml), 1,5-dibromopentane (37 g, 0.19 mol) and tetra-n-butylammonium bisulfate (18.3 g, 0.054 mol). Chromatography of the crude product on silica gel using 20% ethyl acetate/hexane as eluent gave 12 g (69%) of the title compound as an oil.