Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.[H-].[Na+].I[CH2:45][CH2:46][CH3:47]>O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:45][CH2:46][CH3:47])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1ccc(-c2ccc3cc(OCOCCOC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1

Procedure:
3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 100 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. 200 mg (6.7 mmol) of sodium hydride (80% in oil) were added portionwise and stirring was carried out until gas evolution had ceased. 500 μl (6.1 mmol) of iodopropane were then added and the reaction mixture was stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C21H23FN6O2, 410.2
Reaction SMILES: [N+:1]([C:3](=[C:14]1[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH:26]=[CH:27]1)[CH2:22][CH2:21]3)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])#[C-:2].Cl[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N+:1]([C:3]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:6])=[O:5])([C:14]1[C@:15]2([CH3:16])[C@H:17]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH:26]=[CH:27]2)[CH2:22][CH2:21]3)[CH2:18][CH:19]=1)[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[C-:2]
Reactant: ClCOCc1ccccc1
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(COCc1ccccc1)(C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared according to the method described in Example 8a, starting from 17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-1,4-diene-3-one (462 mg, 1 mmol). Yield: 625 mg of a mixture of the title compound and chloromethyl benzylether (1:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCCN1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CCCCN1S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
1,4-Dichloro-7-isoquinolinylsulphonyl chloride (245 mg, 0.83 mmol) was added to a solution of tert-butyl 2(R)-piperidine carboxylate (153 mg, 0.83 mmol) and triethylamine (170 μl, 1.22 mmol) in CH2Cl2 (15 ml), and the reaction stirred at room temperature for 18 h. The solution was diluted with CH2Cl2, washed with 2M hydrochloric acid, saturated Na2CO3 solution and then brine, dried (MgSO4), and evaporated in vacuo. The residual oil was purified by column chromatography upon silica gel using an elution gradient of pentane-EtOAc (100:0 to 90:10), to give tert-butyl (2R)-1-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-2-piperidinecarboxylate, (290 mg, 0.65 mmol) as a colourless film.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.11 g.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:40](=[O:41])[CH2:39][C:37]#[N:38])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)CC#N)CC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol), cyanoacetic acid (9.0 mg, 0.105 mmol), HATU (40.0 mg, 0.105 mmol) in DMA was added DIPEA (36.7 μL, 0.211 mmol) at 23° C. The mixture was stirred at 60° C. for 30 min, cooled to 23° C., filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (21.0 mg, 51.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.6 Hz, 6H), 1.80-1.96 (m, 2H), 2.00-2.17 (m, 2H), 2.64 (t, J=5.6 Hz, 0.9H), 2.76 (t, J=5.7 Hz, 1.1H), 2.84-2.97 (m, 2H), 3.22-3.34 (m, 2H), 3.64 (t, J=5.8 Hz, 1.1H), 3.75 (t, J=5.9 Hz, 0.9H), 4.08-4.14 (m, 1H), 4.16 (s, 0.9H), 4.17 (s, 1.1H), 4.37 (s, 0.9H), 4.43 (s, 1.1H), 4.48-4.57 (m, 1H), 5.76 (br s, 1H), 6.98-7.06 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 471.5.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]2[CH3:49])=[N:41][CH:42]=1>>[CH3:49][C:44]1[N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH:47]=[C:46]([CH3:48])[N:45]=1
Reactant: Cc1cn(-c2ncc(Br)cn2)c(C)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cn(-c2ncc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2)c(C)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.962 min, m/z=526.3; 1H NMR (CD3OD) 0.86 (s, 3H), 1.16 (s, 3H), 1.49 (m, 3H), 2.06 (m, 2H), 2.12 (m, 1H), 2.20 (s, 3H), 2.35-2.48 (m, 2H), 2.82 (s, 3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.07 (m, 2H), 7.19-7.32 (m, 6H), 7.45 (m, 2H), 7.80 (m, 1H), 8.96 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[CH2:34]([N:36](CC)CC)[CH3:35].Cl.C(=N)(OCC)C>ClCCl.CO>[NH:36]=[C:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][CH:25]=2)=[CH:6][CH:5]=1)[CH3:35]
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=N)NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[4-(2-Aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (100 mg) was dissolved in dichloromethane:methanol (2:5, 7.0 mL), treated with triethylamine (0.2 mL) and ethyl acetimidate hydrochloride (135 mg) sequentially and allowed to stir at ambient temperature for 4 h. The reaction mixture was concentrated and fractionated by column chromatography with NH4OH:MeOH:—EtOAc (10:20:70) to afford the title compound (51 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[CH:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.150 g, 0.6376 mmol) and N-(4-chlorophenethyl)-1H-indole-5carboxamide (0.2095 g, 0.7014 mmol) in DMSO (3 mL) was added K2CO3 (0.1322 g, 0.9564 mmol), and the reaction mixture was heated at 120° C. for 30 minutes, then at 130° C. for 1 hour. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate/hexanes to provide tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1-yl)-3cyanophenyl)acetate (0.160 g, 48.82% yield) as a waxy solid. MS (APCI)=514.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([C:11]2[CH:16]=[C:15](C(C)(C)C)[C:14](OCOCCOC)=[C:13]([C:28]([CH3:31])(C)C)[CH:12]=2)[N:3]=1.CN=C=S.CS(C)=O.[CH3:40][CH2:41]CCCC.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([C:11]2[C:12]3[C:13](=[CH:28][CH:31]=[CH:40][CH:41]=3)[CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CNC(=S)n1nc(-c2cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c2)nc1N
Reactant: CCCCCC
Agent: CN=C=S
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=S)n1nc(-c2cccc3ccccc23)nc1N
Yield: 8.9 %

Procedure:
The synthesis method of Example 1-(3) was applied. The compound (13.6 g) obtained in (4) above, methyl isothiocyanate (25 g) and dimethyl sulfoxide (60 ml) were used as reagents. After the reaction, silica gel column chromatography (hexane-ethyl acetate) and recrystallization from ethyl acetate gave 844 mg of white crystals (yield 8.9% from 1-naphthoic acid hydrazide).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5 H, m), 2.02-2.19 (1 H, m), 3.46-3.66 (1 H, m), 3.96-4.12 (1 H, m), 4.24 (1 H, dd, J=9.14, 3.20 Hz)
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:20]=1.O>CN(C)C(=O)C>[C:23]1([C:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[N:20][CH:19]=2)=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ncc(C(=O)c2ccccc2)s1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ncc(C(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Thionyl chloride (80 μl, 1.1 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (150 mg, 0.949 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C. and the mixture is stirred at this temperature for one hour. After addition of 2-amino-5-(phenylcarbonyl)thiazole (130 mg, 0.636 mmol) and equilibration to room temperature, the reaction mixture is stirred for 2.5 hours, then poured into 100 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33% v/v ethyl acetate in petroleum ether (40/60)) to give N-[5-(phenylcarbonyl)thiazol-2-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.10 g, 46%) as pale yellow crystals. These crystals are digested in dichloromethane.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]#[CH:17]>CN(C)C=O.O>[CH2:17]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: OCc1ccc2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 16.6 g of 1,4-benzodioxan-6-methanol in 20 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. 11.8 g of propargyl bromide are then added dropwise. The mixture is stirred for 3 hours at room temperature, cooled in an ice-bath, decomposed with 20 ml of ice-water, diluted with 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The ether extract is washed with water, dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using benzene as the elution agent. There is obtained 6-[(2-propynyloxy)methyl]-1,4-benzodioxan; nD24 = 1.5487.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[CH:9]([CH:10]=[CH:11][C:12]([O:14]C)=[O:13])[CH:8]1[C:16]([OH:18])=[O:17].[CH3:20][C:21]1(C)[CH:23](C=C(Br)Br)[CH:22]1C([O-])=O.O1CCCC1>C1CCCCC1>[CH3:6][C:7]1([CH3:19])[C@@H:9]([C:10]#[C:11][C:12]([OH:14])=[O:13])[C@H:8]1[C:16]([O:18][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:17]
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)[O-]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Temperature: -60 °C
Reaction time: 1 h

Procedure:
60 ml of a 20% solution of butyllithium in cyclohexane were added at -65° C. to a mixture of 26 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate and 175 ml of anhydrous tetrahydrofuran and the mixture was stirred at -60° C. for one hour. A current of carbon dioxide was bubbled through the mixture for 90 minutes and the mixture was poured into an ice-water mixture containing N sodium hydroxide. The alkaline aqueous phase was acidified to a pH of 4 and was extracted with ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was crystallized from petroleum ether (b.p.=60°-80° C. to obtain 8.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-1-carboxylate melting at 144° C.
Reaction SMILES: O(S(C)(=O)=O)S(C)(=O)=O.[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)O)=[O:14])[CH3:11].CCN(CC)CC.[NH2:39][C:40]1[C:41](=[O:48])[N:42]([CH3:47])[CH:43]=[C:44]([Cl:46])[CH:45]=1>C(Cl)Cl.O>[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([NH:39][C:40]1[C:41](=[O:48])[N:42]([CH3:47])[CH:43]=[C:44]([Cl:46])[CH:45]=1)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(Cl)cc(N)c1=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)cn(C)c1=O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ms2O (18.65 mmol) was added at −30° C. to a solution of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) (9.32 mmol) and Et3N (46.6 mmol) in CH2Cl2 (60 mL) and stirred at −30° C. for 15 min. 3-Amino-5-chloro-1-methyl-1H-pyridin-2-one (Step L4) (11.19 mmol) was added and the mixture was stirred at −10° C. for 30 min. The mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic phases were washed successively with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid. ESI-MS: tR=1.37 min, [M+]+462/464 (LC-MS 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]CC=C)[C:14]=3[C:15]=2[CH3:16])[O:9][CH:10]=1)=[O:5])[CH3:2].C1N2CCN(CC2)C1.Cl>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:14]=3[C:15]=2[CH3:16])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C=CCOc1cccc2oc(-c3nc(C(=O)OCC)co3)c(C)c12
Agent: [Rh]
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1coc(-c2oc3cccc(O)c3c2C)n1
Yield: 81.5 %

Procedure:
2-(4-Allyloxy-3-methyl-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester (671 mg) in 80% aqueous ethanol (60 ml) was stirred in the presence of chlorotris(triphenylphosphine)rhodium (63 mg) and triethylenediamine (32 mg) at 90° C. for 6 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 2-(4-hydroxy-3-methyl-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester as a white solid (480 mg). EI-MS: m/z 287 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>>[CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[O:14][C:19]([CH3:20])=[N:16][N:15]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Reactant: CC(=O)OC(C)=O
Product: CCc1c(OC)nc2nc(-c3nnc(C)o3)cn2c1C
Yield: 34 %

Procedure:
Using the procedure of Steps B and C of Example 3, 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide and acetic anhydride were reacted to obtain a 34% yield of 6-ethyl-7-methoxy-5-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([CH2:31][CH2:32][CH3:33])[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N(NC(=O)C(F)(F)F)c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)C(F)(F)F)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
5.0 g (15.19 mmol) of the crude product 402 are treated with 7.42 g (22.77 mmol) of cesium carbonate in 100 ml of DMF under a nitrogen atmosphere. After 30 min, 3.87 ml (22.77 mmol) of 1-iodopropane are slowly added dropwise and the mixture is then stirred at RT for 18 h. After customary work-up, 5.64 g (100%) of 403 are thus obtained as an oil, which is employed directly in stage 4.
Reaction SMILES: O[CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].P(Br)(Br)[Br:17]>>[Br:17][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: BrP(Br)Br
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Product: C[C@H](CBr)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 142.8 %

Procedure:
(R)-2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione (8.75 g, 43 mmol) and phosphorus tribromide (2.73 ml. 29 mmol) were heated at 175° C. for 50 min. To cooled reaction mixture was added ice (50 ml). Thus formed precipitate was filtered, washed with water and dried under vacuum to obtain 11.1 g (97%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 3.85 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 7.88 (m, 4H).
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[C:7]2(O)[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[C:13]=3[CH2:14][CH:6]2[S:5][C:4]1=[N:26][CH3:27]>C(O)(=O)C>[BrH:1].[CH3:27][N:26]=[C:4]1[N:3]([CH3:2])[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[C:13]=3[CH2:14][C:6]=2[S:5]1
Reactant: CN=C1SC2Cc3c(-c4ccc(C(F)(F)F)cc4)cccc3C2(O)N1C
Agent: Br
Solvent: CC(=O)O
Product: CN=c1sc2c(n1C)-c1cccc(-c3ccc(C(F)(F)F)cc3)c1C2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
425.5 mg (1 mmol) of 3-methyl-2-methylimino-7-(4-trifluoromethylphenyl)-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol hydrobromide are suspended in 10 ml of glacial acetic acid and stirred at 100° C. for 3 h. The solvent is then evaporated off in vacuo, and the residue is taken up in water, filtered, washed with water and dried in vacuo. Methyl[3-methyl-7-(4-trifluoromethylphenyl)-3,8-dihydroindeno[1,2-d]thiazol-2-ylidene]amine hydrobromide is obtained with a melting point of 230-233° C.