Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54]>C(Cl)Cl.CO>[CH2:51]([N:52]([CH2:55][CH3:56])[CH2:53][CH2:54][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH3:50]
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-diethylamine hydrochloride. The title compound: ES-MS: 441.9 [M+H]+; single peak at tR=3.41 min (System 2); Rf=0.25 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:8].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=2[O:20][CH3:21])[C:11]1=[O:24].C([BH3-])#N.[Li+].O1CCOCC1.Cl>CO>[ClH:8].[CH:1]1([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=3[O:20][CH3:21])[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a mixture of 200 volume parts of dry methanol and 200 volume parts of cyclohexanone is dissolved 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride and under nitrogen sparging and cooling at 0° C, there is added 9 parts of a molecular compound consisting of 1 mole lithium cyanoborohydride and 2 moles dioxane (LiBH3CN.2C4H8O2). At a constant temperature of 5° C, the reaction mixture is stirred for 2 hours. After the addition of dilute hydrochloric acid, the methanol is distilled off. The remaining mixture is washed with benzene and evaporated to dryness under reduced pressure. The residue is dissolved in ethanol, treated with activated carbon and recrystallized from a mixture of ethanol and ethyl ether. The procedure yields 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 180°-190° C (decomposition).
Reaction SMILES: C(OC)(=O)C[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](OC)=O.[OH2:17]>>[C:5]1([C@@H:4]([OH:17])[CH3:3])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCCCCC(=O)OC
Reactant: O
Product: C[C@H](O)c1ccccc1

Procedure:
Interesterification was carried out in the same manner as in Example 12, except for replacing dimethyl octadecadicarboxylate with 150 g of dimethyl sebacate at 90° C. for 30 hours. The water content of the reaction system was 0.07% by weight, and 87% of the lipase particles had a particle size of 25 to 60 μm. After completion of the reaction, gas chromatography of the reaction mixture revealed that 42 mol % of (R,S)-1-phenylethanol had been converted to its sebacic acid ester. The reaction mixture was treated in the same manner as in Example 12 to remove lipase, and the filtrate was subjected to simple distillation at 90° C. and 3 mmHg. However, it was impossible to isolate (S)-(-)-1-phenylethanol due to co-distillation of other components, such as esters.
Reaction SMILES: [F:1][C:2]1([F:60])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39](N5CCOCC5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])[OH:63].[Na+].[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1([F:60])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:63])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N6CCOCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To 4.30 g (5.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 12, 14 ml of conc. hydrochloric acid, 36 ml of methanol and 40 ml of 1,4-dioxane were added, and the reaction solution was stirred at 70° C. for 1.5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of saturated sodium hydrogencarbonate aqueous solution to which 14 ml of 6 N sodium hydroxide aqueous solution had been added and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1-2/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. Toluene was added to the obtained residue and the precipitate was obtained by filtration to provide 2.60 g of the title compound as a white solid (yield: 78%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[SH:18]>CN(C=O)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[S:18][CH3:8]
Reactant: Fc1cc(S)c(Br)cc1F
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Potassium carbonate (310 mg, 2.22 mmol) and iodomethane (0.138 mL, 2.22 mmol) were added to a solution (10 mL) of 2-bromo-4,5-difluorothiophenol (400 mg, 1.78 mmol) in DMF, and stirred at room temperature overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: OC1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[C:27]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)(N1C=CN=C1)=O>C1COCC1>[N:34]1([CH:27]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]3[CH:7]=[C:6]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=4)[CH:5]=[CH:4][C:3]2=3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et2O and washed with 5% aqueous NaOH, H2O, and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5% MeOH—CH2Cl2) afforded 50.0 mg (31%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 22 h
Yield: 24 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (30 mg, 0.072 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:10) to furnish IV as a yellow oil (7 mg, 24%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(N)=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzamide (which was obtained in Example 147) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.2–1.40 (m, 2 H), 1.70–1.90 (m, 2 H), 2.55–2.95 (m, 5 H), 2.97 (s, 3 H), 3.70–3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.91 (d, J=9.0 Hz, 2 H), 6.99 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.67 (br s, 2 H), 7.72 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 448.9 (MH+); HRMS Calcd. for C21H29N4O5S (MH+): 449.1853. Found: 449.1853.
Reaction SMILES: [CH2:1]([O:8][P:9]([O-:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23]CC)(=[O:22])[CH:20]=[CH2:21].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:11]([O:10][P:9]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(=O)OCC
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of dibenzylphosphite (2.6 mmol) in 10 mL of THF was added ethyl acrylate (3.0 mmol), K2CO3 (16 mmol), and 0.3 mL of (Bn4NH)2SO4 50% w/w. The reaction mixture was stirred at 45° C. overnight. Water was added. The aqueous layer was extracted with ethyl acetate. Organic layer was collected and dried with MgSO4. Solvent was removed to afford a clear oil 3-bis(benzyloxy)phosphorylpropanoic acid in 90% yield. 1H-NMR (CDCl3, 400 MHz): 7.33 (m, 10H), 4.90-5.10 (m, 4H), 3.61 (s, 3H), 2.50-2.60 (m, 2H), 2.00-2.15 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([N:61]=[C:62]=[O:63])=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=2)=[O:63])[CH2:48]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C(C[C@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCN(C(=O)Nc2ccc(F)cc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 73 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as the starting materials in 73% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:23][C:9]1[N:8]([CH2:7][C:4]2[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[S:6][N:5]=2)[C:16]2[C:11]([CH:10]=1)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(Cl)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 327 using 1-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 326) and [3-(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 467 (M+1).
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].[F:26][C:27]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[F:26][C:27]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([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:30]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(F)c4F)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 2,3-difluorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1.CCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:8]2[S:9][C:10]([B:19]([OH:24])[OH:20])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cccc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-trifluoromethyl-benzo[b]thiophene (0.52 g, 0.0026 mol) in THF (30 mL) at −78° C. was added 2.5 M of n-BuLi in hexane (1.4 mL). The reaction was then slowly warmed up to −30° C. over 30 min. and stirred at this temperature for 10 min prior to recooling to −78° C. and treatment with triisopropyl borate (0.7255 g, 0.0038 mol). The reaction was then slowly warmed up to 0° C. then was quenched with saturated ammonium chloride and the solvent removed in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) then this mixture was extracted with DCM. The aqueous solution was acidified using dilute sulfuric acid (2N solution), filtered and the residue dried in vacuo to yield 7-trifluoromethylbenzo[b]thiophen-2-boronic acid. 1H NMR (400 MHz, MeOD) δ ppm 7.55 (1H, t, J=7.45 Hz), 7.75 (1H, d, J=7.07 Hz), 8.02 (1H, s) and 8.17 (1H, d, J=−7.83 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=O)[CH3:2].[CH2:13]([NH2:17])[CH2:14][CH2:15][NH2:16]>>[CH3:2][C:1]12[NH:17][CH2:13][CH2:14][CH2:15][N:16]1[C:6](=[O:8])[C:5]1[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCN
Reactant: CC(=O)c1ccccc1C(=O)O
Product: CC12NCCCN1C(=O)c1ccccc12

Procedure:
16.4 Parts of o-acetyl-benzoic acid and 8 parts of 1,3-propanediamine are heated for 2 hours at 150°-160°. The reaction mixture is then distilled under high vacuum. The 10b-methyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol -6(2H)-one obtained of the formula ##STR35## boils at 120°-123°/0.1 Torr. After recrystallising from ethyl acetate/benzine, it melts at 64.5°. The following compounds are obtained in an analogous manner:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].CO>O>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: CC(C)c1nc(C=O)cs1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Br
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (2.2 g, 14.6 mmol), NaOH (1.5 g) and MeOH (20 mL) was heated to 50° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15A (2.8 g, 94.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][C:26]3[C:22]([C:16]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=4[CH3:14])=[N:23][NH:24][CH:25]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3ccc(Cl)nc23)c1
Reaction time: 14 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (400.4 mg, 1.853 mmol, 1.16 equiv) in dichloromethane (6 mL) was added 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (300.0 mg, 1.602 mmol, 1.0 equiv) and triethylamine (0.70 mL, 5.0 mmol, 3.1 equiv) at room temperature. After 14 hours, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to yield 5-chloro-N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=367.1.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH3:17])=[CH:12]2)=[O:5].BrN1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N.BrCC1C=[N:57][C:58]2C(C=1)=CC=C[C:59]=2[NH:65][C:66](=O)C1C(Cl)=CC=CC=1Cl.N1C=CN=C1>C(Cl)(Cl)(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][N:57]1[CH:58]=[CH:59][N:65]=[CH:66]1)=[CH:12]2)=[O:5]
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reactant: O=C(Nc1cccc2cc(CBr)cnc12)c1c(Cl)cccc1Cl
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Agent: O=C1CCC(=O)N1Br
Agent: c1c[nH]cn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=C(Nc1cccc2cc(Cn3ccnc3)cnc12)c1c(Cl)cccc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-methylquinoline (104 mg), N-bromosuccinimide (67.1 mg) and 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (20.1 mg) in carbon tetrachloride (3 ml) was refluxed for 2 hours. After cooling, the mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give a residue containing 3-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline. The residue was dissolved in ethylene chloride, and imidazole (64.1 mg) was added thereto. After stirring for 2.5 hours at 60° C., the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-dichloromethane) to give 8-(2,6-dichlorobenzoylamino)-3-(imidazol-1-ylmethyl)quinoline (36.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH:20](I)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 77.5 %

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (10 g), isopropyl iodide (7 g) and anhydrous potassium carbonate (5.2 g) were dissolved in acetonitrile (100 ml), and the resultant solution was heated under reflux for 2.5 hours. After cooling, the reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 9 g of N-(2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl). M.P. 62.8° C.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:32]1[O:33][B:29]([OH:30])[C:18]2[CH:19]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:21]=[C:14]([F:13])[C:15]1=2)[CH3:12]
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)cc(F)c2C=O)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(F)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a mixture of zinc powder (0.98 g, 15.0 mmol) in anhydrous THF (30 mL) was added TMSCl (0.39 mL, 3.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and then cooled to 37° C. Ethyl 2-bromoacetate (1.35 mL, 12.0 mmol) was added at 37° C. and the reaction mixture was stirred at this temperature for 30 min. To a solution of 2-fluoro-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.05 g, 3.0 mmol) in anhydrous THF (40 mL) was added dropwise above prepared solution at −78° C. The reaction was allowed to stir at room temperature for 1.5 h and quenched by addition of aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/3) on silica gel to give the title compound as a yellow solid. (0.89 g, Yield: 87.9%). MS (ESI) m/z=339 [M+H]+.