Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cc(Cl)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,5-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)C.[OH-].[Na+].O>C1COCC1.C(O)C>[Br:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:29])=[O:3])=[CH:7][CH:8]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of (E)-{4-[3-(4-bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid ethyl ester (example 11) (700 mg, 1.6 mmol) in THF (5 m) and ethanol (5 ml) was added 1N, NaOH (5.0 ml) and the reaction mixture was stirred for 1 h at 60° C. for 1 h and at room temperature over night. The reaction mixture was added water and the organic solvent evaporated. 1 N HCl was added to pH ˜1-2 and the product extracted with dichloromethane/isopropanol (19:1). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in toluene/petroleum ether (1:1) and 490 mg (70%) of the title compound was isolated by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
A 500 mL round bottom flask was charged with 4-hydroxybenzaldehyde (40 g, 328 mmol) and DMF (250 mL). 4-methoxybenzyl chloride (57.8 mL, 426 mmol) was added, followed by potassium carbonate (90 g, 656 mmol). The reaction mixture was stirred at room temperature for 5 h then poured into ice water (2.5 L). The product was collected by filtration and rinsed with water. After drying thoroughly, 78 g (98%) of aldehyde 12.1 was obtained as a light yellow powder. 1H NMR(400 MHz)(DMSO-d6) δ 9.88 (s, 1H); 7.88 (d, 2H, J=8.7 Hz); 7.42 (d, 2H, J=8.8 Hz); 7.21 (d, 2H, J=8.8 Hz); 6.97 (d, 2H, J=8.6 Hz); 5.16 (s, 2H); 3.77 (s, 3H). MS ESI (pos.) m/e: 243.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][S:5]([CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])(=O)=O.COCCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][S:5][CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13]
Reactant: COC(CS(=O)(=O)CC(OC)OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COCCCl
Agent: [Br-]
Solvent: O
Product: COC(CSCC(OC)OC)OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
In Example 13, involving synthesis of dimethoxyethyl sulfone (DMES), 50 ml 2-chloroethyl methyl ether, 70 g Na2S.9H2O, 17.6 g tetrabutylammonium bromide and 50 ml H2O were mixed into a three-neck flask equipped with magnetic stirrer and reflux condenser, and heated at 70° C. with vigorous stirring. The reaction was continued for overnight. The organic layer was separated and dissolved in chloroform, washed with distilled water several times to remove the ammonium salt and dried over anhydrous sodium sulfate. Solvent was removed using a rotary evaporator, and dimethoxyethyl sulfide was obtained with a yield of 63%. The sulfide was oxidized with H2O2 and acetic acid, as described in Example 1, to obtain the corresponding sulfone, dimethoxyethylsulfone (DMES).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([NH:15][S@@](C(C)(C)C)=O)[C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)(C)(C)C.[ClH:24].O1CCOCC1>CO>[ClH:24].[NH2:15][C@H:8]([C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)[CH2:7][OH:6]
Reactant: Cc1cnc([C@H](CO[Si](C)(C)C(C)(C)C)N[S@](=O)C(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc([C@@H](N)CO)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 184 mg of (R)—N-[(1S)-2-{[tert-butyl (dimethyl)silyl]oxy}-1-(5-methyl-1,3-thiazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide in 2 ml of methanol was added 2 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and 1 M hydrochloric acid was added thereto, followed by washing with ethyl acetate. The aqueous layer was concentrated under reduced pressure to obtain 112 mg of (2S)-2-amino-2-(5-methyl-1,3-thiazol-2-yl)ethanol hydrochloride.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl-].[NH4+]>C1COCC1>[C:10]([C:4]([CH2:3][Si:2]([CH3:1])([CH3:12])[CH3:13])([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:11]
Reactant: CCOC(=O)C(C#N)C[Si](C)(C)C
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(C[Si](C)(C)C)C(=O)OCC
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of ethyl 3-(trimethylsilyl)-2-cyanopropionate (2.26 g, 11.4 mmol) obtained in Example 13 in THF (15 ml) was cooled on ice, and added with sodium hydride (60%, 473 mg, 11.8 mmol) under an argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was added with ethyl bromoacetate (1.39 ml, 12.5 mmol), the mixture was stirred for 30 minutes under ice cooling, and stirring was further continued at room temperature for 20 hours. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (19:1)] to obtain diethyl 2-cyano-2-(trimethylsilylmethyl)succinate (3.22 g, 99%) mentioned in the title as colorless oil.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2]1.[NH2:7][C@H:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[CH:16][C:17]([Cl:22])=[N:18][C:19]=3[CH:20]=2)[O:11][C:10]([CH3:25])([CH3:24])[C@@H:9]1[OH:26].Cl([O-])(=O)(=O)=O.[Li+].C(OCC)(=O)C>O1CCOCC1>[Cl:22][C:17]1[CH:16]=[C:15]([CH3:23])[C:14]2[CH:13]=[C:12]3[O:11][C:10]([CH3:24])([CH3:25])[C@H:9]([OH:26])[C@@H:8]([NH:7][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH3:6])[C:21]3=[CH:20][C:19]=2[N:18]=1
Reactant: CCCC1CO1
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(O)CN[C@H]1c2cc3nc(Cl)cc(C)c3cc2OC(C)(C)[C@@H]1O
Temperature: 70 °C
Reaction time: 25 h
Yield: 59 %

Procedure:
Under nitrogen stream, 1,2-epoxypentane (71 δL, 0.682 mmol) was added to a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (100 mg, 0.343 mmol) and lithium perchlorate (36 mg, 0.343 mmol) in dioxane (0.50 mL) at room temperature, and the resulting mixture was stirred at 70° C. for 25 hours. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting reaction solution was washed with saturated sodium hydrogencarbonate aqueous solution and then with saturated sodium chloride aqueous solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(N2CCOCC2)c(CN2CCNCC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[5-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (2.90 g, 7.32 mmol, 1.00 equiv), dichloromethane (35 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (7 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to yield 2.60 g (crude) of 4-[4-chloro-2-(piperazin-1-ylmethyl)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32].CN1C=CN=C1>CC#N>[F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:32][C:28]4[S:27][CH:31]=[CH:30][N:29]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: Nc1nccs1
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
A solution of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.334 g, 0.829 mmol) and thiazol-2-amine (0.249 g, 2.488 mmol) in 4 mL MeCN was placed under argon and was treated with 1-methylimidazole (0.081 ml, 0.829 mmol). After stirring for 3 hours at room temperature, LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (0.171 g, 0.367 mmol, 44.2% yield). 1H NMR (MeCN-d3) δ: 9.42 (s, 1H), 8.52 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.38 (d, J=5.4 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 6.93-7.24 (m, 2H), 6.64 (d, J=4.7 Hz, 1H), 3.70-3.73 (s, 3H); (M+H)+=467.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(=O)CC.CO>[C:25]1([S:31]([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]3[CH:23]=[CH:24][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)[CH2:17][CH2:18]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Solvent: CO
Solvent: CCC(C)=O
Product: O=S(=O)(c1ccccc1)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg, 0.30 mmol) was dissolved in 2-butanone (5 ml), treated with benzene sulfonyl chloride (57 mg, 0.32 mmol) and allowed to stir at room temperature under argon for 2 hours. The reaction mixture was diluted with methanol and passed down an SCX column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (91 mg). MS(ES+) m/e 472 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.O>[O:5]([CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH2:1])[Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(CN)CO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution at 0° C. of 0.500 g (4.85 mmol) of 3-amino-2,2-dimethylpropanol (CAS 26734-09-8) in 12 ml of dichloromethane are added 0.059 g (0.48 mmol) of dimethylaminopyridine and 1.35 ml (9.7 mmol) of triethylamine. 1.60 g (5.82 mmol) of tert-butyldiphenylsilyl chloride dissolved in 5 ml of dichloromethane are then added dropwise. The mixture is stirred for 30 minutes at 0° C. and then for 2 hours at room temperature. 20 ml of water are then added. The organic phase is separated out by settling, washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give an oil, which is chromatographed on a column of aminopropyl silica gel, eluting with a mixture of 0 to 10% methanol in dichloromethane, to give 1.20 g of 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylamine in the form of a colourless oil.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)C(C)C)C.[C:55](Cl)(=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([NH:45][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](NC(=O)C(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of (3S,5R)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (374 mg, 0.62 mmol), N-ethyldiisopropylamine (503 μl, 2.94 mmol) and 4-dimethylaminopyridine (31 mg) in CH2Cl2 (8 ml), pivaloylchloride (126 μl, 1.02 mmol) is added. After stirring for 14 h at RT, the mixture is diluted with CH2Cl2. The organic layer is washed with 1N HCl and saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (6 ml) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 ml/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous layer is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish resin. MS: 469.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[CH3:22][C:23]([C:25]([O:27]C)=O)=C>O.C(OCC)(=O)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:2][CH2:7][CH2:6][CH2:22][CH2:23][C:25]([O:19][CH2:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:21])\[CH3:20])=[O:27]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: C=C(C)C(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
An aqueous phase was prepared by dissolving 0.5 g of poly (vinyl alcohol) in 50 ml water saturated by 6 ml of ethyl acetate. An organic phase was prepared by dissolving 0.075 g Retinol Palmitate, 0.1 g mineral oil, 0.01 g of an antioxidant (chosen from BHA, BHT, tocopherol or their mixture) and 0.815 g PMMA in 5 ml of ethyl acetate. The organic phase was poured into the aqueous phase while stirring and then 100 ml of fresh water were added. The microcapsules formed were filtered, washed by water and dried at the temperature no higher 20° C. An average diameter of the microcapsules was 40 μm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[CH2:25][O:24][CH3:23])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)no1
Yield: 48.1 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (50 mg, 0.16 mmol) and phenyl 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from Example 130A (50 mg, 0.17 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative silica gel TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (38 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.50 (s, 1H), 3.99 (s, 6H), 3.38 (s, 2H), 3.23 (s, 3H), 1.24 (s, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH:3]([CH:16]1[NH:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[ClH:1].[CH:3]([CH:16]1[CH2:17][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:20][N:21]1[CH2:32][C:33](=[O:34])[NH2:35])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(CC(N)=O)C(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A mixture of 3-benzhydryl-1-(2-methoxybenzyl)piperazine dihydrochloride (44.5 mg), bromoacetamide (20.7 mg) and potassium carbonate (41.5 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (70:1). The fractions containing the objective compound were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydryl-1-carbamoylmethyl-4-(2-methoxybenzyl) piperazine dihydrochloride (21.6 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[O:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(C(=O)c2ccnc(Cl)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc(C(O)c2ccnc(Cl)n2)c1
Reaction time: 1.67 h
Yield: 95.9 %

Procedure:
3-[(2-chloropyrimidin-4-yl)carbonyl]benzonitrile (3 g, 12.31 mmol) was dissolved in 90 mL dry methanol and cooled to 0 C. Sodium borohydride (Acros, 0.512 g, 13.54 mmol) was dissolved in 30 mL dry methanol and added slowly via syringe, and the reaction mixture stirred at 0 C for 100 min. Additional sodium borohydride (0.256 g, 6.77 mmol) was dissolved in 15 mL dry methanol and added via syringe. After 20 minutes the reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate. The resulting mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The aqueous portion was extracted with methylene chloride (3×), and the combined organic portion dried over sodium sulfate and concentrated in vacuo to give 3-[(2-chloropyrimidin-4-yl)(hydroxy)methyl]benzonitrile (2.9 g, 96%). LRMS m/z (M+H) Calcd: 246.7, found: 246.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Clc1ccccc1I
Product: Clc1ccc2ccn(-c3ccccc3Cl)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:26][CH3:27]
Reactant: CCC(N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(CC)CO)s1
Yield: 52 %

Procedure:
As described for example 102, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using rac-2-amino-1-butanol instead of 1,1-dimethylhydrazine, to the title compound (98 mg, 52%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane). MS: m/e=378.3 [M+H]+.