Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2cc[nH]c12
Temperature: 40 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-nitro-benzene (14 g, 0.059 mol) in 400 mL THF at −40° C. was added dropwise vinylmagnesium bromide (177 mL of 1.0M solution in THF, 0.177 mol). The reaction mixture was stirred for 2 hrs at 40° C. Aqueous NH4Cl was added and the mixture extracted with ether. The organic phase was dried over Na2SO4, concentrated and the residue purified by silica gel column chromatography to give the title compound (6 g, 44%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH-].[K+]>O1CCOCC1.O>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (25.7 g.) in dioxan (500 ml.) was treated with potassium hydroxide (10 g.) and water (250 ml.) and the mixture allowed to stand at room temperature for 1 hour. After a further 1 hour at 40° the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina. Crystallisation from acetone-petrol gave pure 3β-hydroxy-5α-pregn-16-ene-11,20-dione (17.65 g.) as small plates m.p. 217.5°, [α]D + 82.9°. (c 1.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-chloro-4-fluoro-1-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 504.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:41]([C:32]2[CH:33]=[CH:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)=[O:42])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc2ccccc2c1

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.5 g, 1.4 mmol) was dissolved in 1,4-dioxane (20 ml) and triethyl amine (0.29 g, 2.9 mmol) and 2-naphthoyl chloride (0.41 g, 2.2 mmol) were added. Solution was heated under reflux for 4 hr and solvent removed under reduced pressure. Product was subjected to column chromatography on silica gel and the title compound was eluted with hexane-ethyl acetate (8:2; 0.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[C:8]([NH2:19])[C:7]=1[NH2:20].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:7]2[N:20]=[C:30]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)[NH:19][C:8]=2[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1N
Reactant: O=Cc1nccs1
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc2[nH]c(-c3nccs3)nc12

Procedure:
The entitled compound was obtained as a yellow solid in the same method as in Example 67 or in accordance with the method or by combining it with an ordinary method but using 3-(2-methoxyphenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 67 (step 3) and 2-thiazolecarboxaldehyde.
Reaction SMILES: [N:1]1([C:6]2[CH:43]=[CH:42][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([C:24]3[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[OH:23])=[CH:16][C:15]=4[CH3:40])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:44]1[CH2:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([C:12]2[C:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:43][CH:42]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[C:15]([CH3:40])[CH:16]=[C:17]([C:22]([C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)([C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[OH:23])[CH:18]=3)[N:13]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: C1CNC1
Reactant: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(N3CCC3)nc12
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.321 mmol, Intermediate 68), azetidine (183 mg, 3.21 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the solvent and excess azetidine were removed by reduced pressure distillation. The crude residue was taken up into EtOAc, then extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O, 643.2. m/z found, 644.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.82 (d, J=2.2 Hz, 1H), 7.90-7.86 (m, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.61-7.58 (m, 1H), 7.58-7.54 (m, 2H), 7.36 (dd, J=2.3, 1.1 Hz, 1H), 7.19-7.15 (m, 2H), 7.14 (d, J=1.1 Hz, 1H), 6.73 (s, 1H), 6.45-6.40 (m, 1H), 6.24 (d, J=1.1 Hz, 1H), 4.29 (s, 2H), 4.13 (t, J=7.5 Hz, 4H), 3.33 (s, 3H), 2.58 (s, 3H), 2.28-2.19 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>CN1C(=O)CCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[C:2]([OH:12])[CH:3]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Oc1cc(O)c2ccccc2n1
Solvent: CN1CCCC1=O
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Yield: 32 %

Procedure:
2,4-quinolinediol (10.0 g, 62.1 mmol) and 3,4-dichloroaniline (13.1 g, 80.7 mmol) were heated to 190° C. in 25 mL NMP for 48 h. After heating was discontinued, solids began to precipitate. These were collected, treated with 8.5 mL of HCl in isopropanol and sonicated in a 4:1 mixture of acetone:isopropanol. After 2.5 h of sonication, the solids were collected. The sonication cycle was repeated to afford 6.79 g of material (19.9 mmol, 32%). 1H NMR (300 MHz, DMSO): 12.7 (s,1 H), 9.34 (s, 1 H), 8.41 (d, 1 H, J=9 Hz), 7.71 (m, 3 H), 7.6 (d, 1 H, J=8.1 Hz), 7.44 (m, 2 H), 6.25 (s, 1 H), 6.08 (broad s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14].ClCCl>O1CCCC1>[CH3:14][O:13][Si:12]([CH2:11][CH2:10][CH2:9][C:5]1[N:4]=[CH:3][NH:2][N:1]=1)([O:17][CH3:18])[O:15][CH3:16]
Reactant: CO[Si](CCCI)(OC)OC
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[Si](CCCc1nc[nH]n1)(OC)OC
Reaction time: 4 h

Procedure:
5 g (72 mmol) of 1,2,4-triazole were dissolved in 100 ml of absolute tetrahydrofurane and 1.73 g (72 mmol) of sodium hydride were added. The reaction mixture was stirred for 4 hours, after which 10 ml of iodopropyltrimethoxy silane (52 mmol) were added and the reaction mixture was heated under reflux for 18 hours. 20 ml of dichloromethane were then added and the reaction mixture was filtered. The solvent was removed at 150-155° C. under reduced pressure (8 mbar) and then filtered. The yield was 6.4 g (50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:21]4[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=4)[CH:17]=[N:18][C:19]=3F)=[CH:10][CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[O:36]1CCOCC1.Cl>O>[CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:36])[NH:18][CH:17]=[C:16]([C:21]4[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=4)[CH:15]=3)=[CH:10][CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1COCCO1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4nccc(C#N)n4)cnc3F)cc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4nccc(C#N)n4)c[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A resealable tube was charged with (S)-2-(5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-6-fluoropyridin-3-yl)pyrimidine-4-carbonitrile (0.055 g, 0.12 mmol), dioxane (3.0 mL) and water (1.00 mL). Concentrated hydrochloric acid (37%)(0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture stirred at 100° C. for 1 hour. The reaction mixture was then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-2-(5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidine-4-carbonitrile (0.044 g, 0.095 mmol, 80% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.65 (s, 3H), 5.49 (s, 1H), 7.22-7.45 (m, 5H), 7.50-7.61 (m, 2H), 7.63-7.76 (m, 2H), 7.93 (d, J=4.89 Hz, 1H), 8.28-8.47 (m, 2H), 9.11 (d, J=4.99 Hz, 1H), 12.33 (br.s., 1H). m/z (ESI) 464 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18](=[O:20])[NH:22][C:23]3[CH:28]=[C:27]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]=3[O:38][CH3:39])[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(N)n(-c2cc(C(=O)O)ccc2C)n1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N)n(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
5-Amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (46 mg, 0.159 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (67 mg, 0.175 mmol) were combined in DMF (500 μL) and stirred for 5 min at room temperature N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (48 mg, 0.175 mmol) was added to the reaction mixture followed by i-Pr2NEt (83 μL, 0.477 mmol). The solution was stirred at room temperature for 48 h then poured onto saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by semi-prep HPLC provided the title compound (41 mg, 48%) as a yellow solid (TFA salt): mp 104-111° C. (dec.); ESI MS m/z 544 [C26H33N5O6S+H]+; HPLC>98%, tR=20.79 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: CCOC(=O)CC(=O)c1cc(Br)c(OC)cc1OC
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) obtained in Step 3 of Example 1 and N,N-dimethylformamide dimethyl acetal (44.6 g) were dissolved in toluene. The solution was stirred at 95° C. for 16 hr, and the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to room temperature to give a solution of ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate in toluene. The reaction mixture was directly used in the next step.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:17]=1)=[O:15])[CH3:12]>CC(=O)OCC>[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])=[CH:35][CH:36]=2)[N:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 80 %

Procedure:
Phenyl chloroformate (0.95 ml, 1.5 eq.) was added to a stirred solution of 2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (1.15 g, 1 eq.) in EA (20 ml) and NaHCO3(sat) (20 ml). The mixture was reacted at room temperature for 2 hrs. The reaction mixture was diluted with NaHCO3(sat) and extracted with EA. The organic solution was washed with brine, was dried (MgSO4), filtered and concentrated under reduced pressure to give a crude carbamate (1.21 g, 80%).
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[C:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:4]=[CH:3][C:2]=1[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(C)c(C)c1

Procedure:
Orthoxylene (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (160 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][C:57]([NH:59][CH3:60])=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][C:57](=[O:58])[NH:59][CH3:60])=[CH:13][CH:12]=1
Reactant: CNC(=O)CCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: CNC(=O)CCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.30 g tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.16 g of 3-(2-hydroxyphenyl)-N-methylpropionamide are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.61.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[CH2:13](O)[CH2:14][OH:15].P(=O)(O)(O)O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:14]1[O:15][CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[O:8][CH2:13]1
Reactant: O=Cc1ccccc1OCCCl
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: ClCCOc1ccccc1C1OCCO1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of 46.5 g of 2-(2-chloroethyloxy)benzaldehyde and 33.2 g of ethylene glycol in 500 ml of benzene in added 0.5 ml of 85% phosphoric acid, and the mixture is refluxed with stirring for about 18 hours while removing the produced water. After the reaction, the reaction mixture is cooled with ice and is made alkaline with saturated sodium bicarbonate solution to separate into two layers. The benzene layer is taken, washed with saturated saline solution, dried and then distilled to remove the solvent. The crude product thus obtained is distilled to give 56 g of 2-(2-chloroethyloxy)benzaldehyde ethyleneacetal (yield: 97%) as a colorless oil. b.p. 130°-135° C./0.3 mmHg.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[N:17]1([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Temperature: 25 °C

Procedure:
To a stirred solution of 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one in dry toluene at room temperature was added piperazine (Aldrich) followed by the dropwise addition of TiCl4. The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution. The resulting mixture was extracted with dichloromethane, and the combined organic phases were then dried (K2 CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:12]1(=O)[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: N=C(NO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(-c2cccc(Cl)c2)no1
Yield: 59.7 %

Procedure:
3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated with succinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at 150° C. for an h. The reaction mixture was cooled down and diluted with ethyl acetate. The organic solution was washed with water and brine, concentrated by vacuum. The residue was triturated with 20% ethyl acetate in hexanes to give 4.0 g (60%) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as white solid. ). 1H-NMR(CDCl3) d(ppm): 8.08 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide: This acid was reacted with iodoethane (1.6 g, 10.5 mmol) and K2CO3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min to form 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid ethyl ester. The ethyl ester was then treated with 37% hydrazine (2 ml) in ethanol (5 ml) at 80° C for2 h to give 595 mg (65% in 3 steps) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide as off-white solid 1H-NMR (CDCl3) d(ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95 (w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:15]
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CCN1CCNCC1
Product: CCN1CCN(Cc2ccc(NC(=O)C(F)(F)F)cc2C(F)(F)F)CC1

Procedure:
Reaction of N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (Stage 128.3) with N-ethylpiperazine gives the title compound: MS: [M+1]+=384; 1H-NMR (CDCl3): 8.0 (sb, HN), 7.8 (m, 3H), 3.63 (s, 2H), 2.51 (sb, 8H), 2.43 (q, 2H), 1.09 (t, H3C).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: C=CC(=O)O
Product: CCCCN(CCCC)CCC(=O)O
Yield: 98 %

Procedure:
After completion of the reaction, acrylic acid and di-n-butylamine were assayed by gas chromatography. As a result, formation of 152.5 g (yield 98%) of N,N-di-n-butyl-β-alanine was confirmed, with the rates of conversion of acrylic acid and di-n-butylamine being 98% and 98%, respectively.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:12])[CH2:4][C:5]#[C:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9]>N1C2C(=CC=CC=2)C=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCO>[Cl:1][CH2:2][C@H:3]([OH:12])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)CC#CC[C@@H](O)CCl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: C[Si](C)(C)C/C=C\C[C@@H](O)CCl
Yield: 98.5 %

Procedure:
13.04 g (63.7 mmol) of (R)-1-Chloro-6-trimethylsilanyl-hex-4-yn-2-ol was dissolved in 260 ml of abs. EtOH and hydrogenated, in the presence of 9 drops of quinoline, over 1.70 g of Lindlar catalyst at ambient temperature and 1 atm of H2. The progress of the reaction was followed by GC. After 2 h the reaction mixture was filtered and the solvent removed i.V. Short flash chromatography (SiO2, hexane/AcOEt=85/15) afforded 12.97 g of (Z)-(R)-1-chloro-6-trimethylsilanyl-hex-4-en-2-ol as colorless oil.