Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([CH2:12]O)[N:6]2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:29][C:30]([F:40])([F:39])[CH2:31][CH2:32][CH:33]1[CH2:37][NH:36][C:35](=[O:38])[NH:34]1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([CH2:12][N:36]3[CH2:37][CH:33]([CH2:32][CH2:31][C:30]([F:39])([F:40])[F:29])[NH:34][C:35]3=[O:38])[N:6]2[N:5]=1
Reactant: O=C1NCC(CCC(F)(F)F)N1
Reactant: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCc1nn2c(CN3CC(CCC(F)(F)F)NC3=O)c(C(F)(F)F)nc2s1
Temperature: 110 °C
Yield: 64 %

Procedure:
[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 (3.26 g, 0.122 mol, 1 eq) and p-toluenesulphonic acid (2.10 g, 0.122 mol, 1 eq) are successively added to a solution of 4-(3,3,3-trifluoropropyl)imidazolidin-2-one a10 (2.22 g, 0.122 mol, 1 eq) in toluene (450 ml). The mixture is heated at 110° C. overnight. The reaction is not complete and another portion of intermediate a10 (1 g, 5.49 mmol, 0.45 eq) is added. The mixture is heated at 110° C. overnight, then the solvent is evaporated under reduced pressure. Water is added to the residue, the mixture is extracted with CH2Cl2, the organic layer is dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford 336 mg of 1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)imidazolidin-2-one 5 as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][NH:38][CH:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCC(N)CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNC3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1-methylpiperidin-4-amine.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][C@H:19]1[CH2:38][N:23]2[C:24]3[C:29]([C:30]([CH2:31][C:32]([O:34]CCC)=[O:33])=[C:22]2[CH2:21][CH2:20]1)=[CH:28][CH:27]=[CH:26][CH:25]=3>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:18]([CH3:17])[C@H:19]2[CH2:38][N:23]3[C:24]4[C:29]([C:30]([CH2:31][C:32]([OH:34])=[O:33])=[C:22]3[CH2:21][CH2:20]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from diphenylacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 453.
Reaction SMILES: [C:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20](OC(=O)C)(=[O:22])[CH3:21]>S(=O)(=O)(O)O>[C:20]([O:19][C:13]1[CH:12]=[CH:11][C:10]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])(=[O:22])[CH3:21]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
1 g of 5-n-octanoylsalicylic acid is suspended in 15 ml of acetic anhydride. After addition of 2 drops of concentrated sulphuric acid the solution is heated to 100° C. for 15 minutes. The solution is poured onto 150 ml of crushed ice. After extracting with ether, washing the organic phase with the water, drying over sodium sulphate and evaporating, 1 g of a white crystalline product is obtained. The yield is 85%. The recrystallization is done from a 50/50 mixture of toluene and petroleum ether. The melting point is 130° C.
Reaction SMILES: [C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13](I)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1)#[CH:23]>>[C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13]([C:23]#[C:22][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Reactant: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 7-tert.-butyl-5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidine (70 mg, 0.17 mmol) and 5-ethynyl-thiophene-2-sulfonamide (example D.3) (32 mg, 0.17 mmol) according to general procedure II. Obtained as a yellow solid (28 mg, 28%). MS (ISP) 471.1 [(M+H)+]; mp 253-255° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:28])[C:16](=[O:27])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[CH:18][C:8]2=1)=O.[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([NH2:36])=[S:35]>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[C:16](=[O:27])[N:15]([CH3:28])[C:9]2[N:10]([CH3:14])[C:11]3[C:7]([C:8]=2[CH:18]=1)=[CH:6][C:5]([C:3]1[N:36]=[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])[S:35][CH:2]=1)=[CH:13][CH:12]=3
Reactant: COCCNC(N)=S
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Product: COCCNc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as for Example 21 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 1-(2-methoxyethyl)-2-thiourea.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(Br)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-bromobenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH2:26]([N:23]([CH2:24][CH3:25])[C:21]1[CH:20]=[C:19]([CH3:28])[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)[CH3:27]
Reactant: CCN(CC)c1cc(C)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: CCN(CC)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 65 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (67 mg, 0.33 mmol) and (2-chloro-6-methyl-pyrimidin-4-yl)-diethyl-amine (67 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 65% yield as a light yellow viscous oil. MS ISP (m/e): 367.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.15 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.32 (d, 1H), 7.16 (d, 1H), 7.01 (s, 1H), 6.00 (s, 1H), 3.78 (s, 3H), 3.51 (br q, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 1.13 (t, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][O:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:16][O:15][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: NC1COC(c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC2COC(c3ccccc3)C2)c1Cl

Procedure:
1.50 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.39 g (8.5 mmol) of 4-amino-2-phenyltetrahydrofuran and 2 ml (14 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After the mixture had been dried and concentrated, the residue was purified by column chromatography using petroleum etherlethyl acetate (9:1, 8:2). This gave 1.63 g (63% of theory) of a colorless oil (diastereomers 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:14]([F:19])[C:15](OC)=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:14]([F:19])[CH2:15][OH:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C2(C=C(F)C(=O)OC)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOc1ccc(C2(C=C(F)CO)CC2)cc1
Yield: 73.4 %

Procedure:
The method of Example 9 was repeated using 1-(4-ethoxyphenyl)-1-(2-fluoro-2-(methoxycarbonyl)ethenyl)-cyclopropane (Example 2) (2.3 g), diethyl ether (20 ml) and lithium aluminium hydride (0.55 g) to yield the title compound (1.51 g, 74%).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C=O)C>[ClH:2].[ClH:1].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: c1c[nH]cn1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCn4ccnc4)cc23)c1
Yield: 67.7 %

Procedure:
The title product of Example 30 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (125 mg) was chromatographed on silica using 10% methanol/CH2Cl2 to provide 86 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid dihydrochloride salt (95 mg; 78%; M.P. 85°-100° C. (dec); LC-MS: 430 (MH+); anal. RP18-HPLC RT: 4.13 min.).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: ClCc1nc2cccnc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (680 mg, 3.7 mmol), 2-(1-piperazinyl)benzonitrile (823 mg, 4.4 mmol), and DIEA (1.3 mL, 7.4 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.23 (m, 4H) 4.09 (s, 2H) 7.13 (m, 1H) 7.21 (d, J=8.14 Hz, 1H) 7.59 (m, 2H) 7.71 (dd, J=7.80, 1.70 Hz, 1H) 8.34 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 336 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=3)=[N:4][CH:3]=2)=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CCCCCCc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2ncc(OCc3ccc(CCC)cc3)cn2)cc1

Procedure:
A mixture of 10.2 g of 5-hydroxy-2-(4-n-hexyl-phenyl)-pyrimidine, 8.6 g of 4-n-propylbenzyl bromide, 8.6 g of potassium carbonate and 50 ml of dimethylformamide are warmed at 90° for 10 hours. Conventional work-up gives 2-(4-n-hexylphenyl)-pyrimidin-5-yl p-n-propylbenzyl ether.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)n1ccc2c(C(=O)O)cccc21
Reaction time: 0.5 h

Procedure:
To 1H-Indole-4-carboxylic acid (611, 251 mg, 1.56 mmol) in tetrahydrofuran (3 mL), was added 2.5M n-butyllithium in hexane (1.28 mL, 3.19 mmol) at −78° C. After 30 minutes, dibutyl carbamyl chloride (657 mg, 3.43 mmol) was added and stirred for two hours. The reaction solution was quenched with 1M HCl (aq.) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography using 10% ethyl acetate in hexane to give a white solid (612, 88 mg, 18%). MS (ESI) [M−H+]−=315.1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:4](C(Cl)(Cl)Cl)[CH:3]=1.ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)(O)[C:29](Cl)([Cl:31])[Cl:30]>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=2)[CH:29]([Cl:31])[Cl:30])=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1Cl)(c1ccccc1Cl)C(Cl)(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1C(Cl)(Cl)Cl
Product: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)Cl)cc1

Procedure:
4,4'-dichloro-2-(trichloromethyl) benzhydrol or 1,1-bis(chlorophenyl)2,2,2-trichloroethanol;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([N:37]([CH2:42][CH3:43])[S:38](Cl)(=[O:40])=[O:39])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:38](=[O:40])(=[O:39])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21
Reactant: CCN(CC)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2(C)C
Temperature: 2.5 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (145 mg, 0.38 mmol, cf. example 67) was dissolved in dry dichloromethane (8 mL). Triethylamine (60 μL, 0.45 mmol). The solution was cooled to 0-5° C. and diethylsulfamoyl chloride (71.5 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with dichloromethane (20 mL) and washed with a 1:1 mixture of water and saturated ammonium chloride solution (20 mL). The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:ethyl acetate=180:5). Yield: 96 mg (0.19 mmol, 48.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc(N)nc(C)c1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 2.00 g (16.32 mmol) of 2-amino-4,6-dimethylpyridine in 25 mL of acetonitrile were added 2.90 g (16.32 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature under argon atmosphere for 5 h. The formed precipitate was filtered and dried to afford the expected product as a white solid: yield 2.76 g (84%). 1H-NMR (CDCl3) δ 6.22 (s, 1H), 4.39 (br, 2H), 2.48 (s, 3H), 2.25 (s, 3H); 13C-NMR (CDCl3) δ156.34, 155.23, 148.64, 112.26, 108.10, 25.10, 23.30.
Reaction SMILES: FC(F)(C(F)(F)[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])CCCCCCOC1(C)C=CC(S([O-])(=O)=O)=CC1.[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](F)(F)[C:46](F)(F)[C:47]([F:53])([F:52])[C:48]([F:51])([F:50])F)[CH:36]=[CH:35][C:34]=1[I:58]>>[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([F:52])([F:53])[C:48]([F:50])([F:51])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:36]=[CH:35][C:34]=1[I:58]
Reactant: CC1(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Reactant: Fc1c(I)ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Product: Fc1c(I)ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Yield: 89 %

Procedure:
2,3-Difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) was prepared from 4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-tosylate (9B), prepared as described in [Sakaigawa], as described in the preparation of 2,3-difluoro-1-iodo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (10A) yielding 2,3-difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) as a colorless oil (89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.IC.[C:31](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:31])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCc1ccc(N(C)Cc2cccc(-c3c(C)cccc3C)c2)cc1
Yield: 47.9 %

Procedure:
To a solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.598 g, 1.60 mmol) and iodomethane (0.498 mL, 8.00 mmol) in acetone (10 mL) was added potassium carbonate (0.332 g, 2.40 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 6 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (0.297 g, yield 48%) as a yellow oil.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[Br:27])=[CH:17][C:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.CCO.[OH-].[Na+]>O>[Br:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[CH:17]=1
Reactant: COc1cccc(Sc2cnc(NC(=S)NC(=O)c3ccccc3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Sc2cnc(NC(N)=S)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-benzoyl-3-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (10.3 g, 17.6 mmol) and EtOH (125 mL). 3M Sodium hydroxide (11.7 mL, 35.2 mmol) was added and heated to 50° C. overnight. The reaction was cooled to room temperature and poured into 750 mL water and stirred vigorously for 1 hour. The solids were filtered to afford the title compound (6.5 g, 76.8% yield).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[C:1]([NH:8][C@@H:12]([C:13]#[CH:14])[CH2:11][OH:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C#C[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (200 mg, 0.89 mmol) (Example 93A above) in a mixture of MeOH (25 mL) and water (2 mL) was treated with p-toluenesulfonic acid monohydrate (16 mg, 0.09 mmol) according to the procedure that described above in Example 104A. (Yield 120 mg, 73%).
Reaction SMILES: [OH:1][C:2]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])[C:3](O)=[O:4].[NH2:16][C@@H]1C(=O)N(CC(F)(F)F)C2C=C(F)C=CC=2O[C@@H]1C>>[OH:1][C:2]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])[C:3]([NH2:16])=[O:4]
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Product: CC(O)(C(N)=O)C(=O)NCCC(F)(F)F

Procedure:
N-[(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide was obtained as mixture of epimers according to the procedures described for example 2b using racemic 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid and (6R,7S)-7-amino-2-fluoro-6-methyl-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one. The epimers were separated by chromatography on Chiralpak AD using ethanol/heptane 15:85 to yield (−)-N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide, entity A, MS m/e (%): 504.0 (M+H+, 100), as first eluting fraction, and (−)-N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide, entity B, as second eluting fraction, MS m/e (%): 504.0 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([O:15]CCO)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
Crude 2-hydroxyethyl 4-(4-chlorophenyl)pyrrole-2-carboxylate (3 g.) was heated on a steam bath with potassium hydroxide (2 g.) in 25 ml. of water and 25 ml. of ethanol for 30 minutes. The balance of the ethanol was evaporated in vacuo, chloroform (25 ml.) was added and 4-(4-chlorophenyl)pyrrole-2-carboxylic acid (723 mg., m.p. 219°-222° C., ir(KBr): 3390, 3077 and 1695 cm.-1, m/e 221/223) recovered by filtration.