Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](O)[CH3:9].C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([F:30])[CH3:9]
Reactant: CC(O)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 5-chloro-6-(1-hydroxyethyl)-4-[1-(4-difluoromethoxyphenyl)-ethylamino]pyrimidine, and to the mixture was added dropwise 0.4 g of diethylaminosulfur trifluoride under ice cooling. The mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
There were prepared 1.0% liniments by dissolving in ethanol the monoester with stearic acid obtained in Reference Example 1 (Example 1), the monoester with oleic acid obtained in Reference Example 2 (Example 2), the monoester with myristic acid obtained in Reference Example 3 (Example 3), the monoester with caprylic acid obtained in Reference Example 4 (Example 4) or a pure kojic acid (Comparative Example 1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:49])[CH3:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CCOC(C)=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:47]([CH3:48])[CH3:49])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:50])[C:19]2=[O:51])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
To a solution of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester (391.9 mg, 0.674 mmol) in dioxane (8 mL) was added 4M HCl in dioxane (6 mL). The reaction was stirred at room temperature for 24 hours and was diluted with EtOAc. The organic solution was washed with aqueous NaHCO3 and brine, was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 10% MeOH in EtOAc) provided 260.9 mg of 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture. 1H NMR (CD3OD) δ 7.90 (d, 1H), 7.65 (d, 2H), 7.34-7.54 (m, 12H), 7.22 (t, 1H), 7.13 (t, 1H), 6.99 (d, 1H), 4.74 (m, 1H), 465 (d, 1H), 4.42 (t, 1H), 3.92-4.12 (m, 3H), 0.99 (m, 6H); MS 582.7 (M+1), 580.4 (M−1).
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]([CH2:13][C@H:14]1[O:23][CH:18]([O:19][C:20](=O)[CH3:21])[C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@H:15]1[O:32][C:33](=[O:35])[CH3:34])=[N+:11]=[N-:12].[CH:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=C(O)C=1.CCOCC>C(Cl)Cl>[C:25]([O:24][C@@H:17]1[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@@H:15]([O:32][C:33](=[O:35])[CH3:34])[C@@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:23][C@@H:18]1[O:19][C:20]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[CH:36][CH:21]=1)(=[O:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)OC1O[C@H](CN=[N+]=[N-])[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 15.4 %

Procedure:
Boron trifluoride diethyl etherate (80 μl, 0.70 mmol) was added to a stirred solution of 6-azido-6-deoxy-1,2,3,4-tetra-O-acetyl-D-galactopyranose 36 (α:β, 1:1) (52 mg, 0.139 mmol) in DCM (5 mL). The solution was stirred under argon at RT. After 20 min a solution of p-nitrophenol (19 mg, 0.14 mmol) in DCM (5 mL) was added to the reaction mixture and stirring under argon maintained. After 65 min, t.1.c. (DCM:ether, 60:1) indicated formation of two products (Rf 0.1, 0.4) with some remaining starting material (Rf 0.3). The DCM was removed in vacuo. The residue was diluted with chloroform (30 mL), washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:ether, 60:1) to afford p-nitrophenyl 2,3,4-tri-β-acetyl-6-azido-6-deoxy-α-D-galactopyranoside 40 (9.7 mg, 14%) as a colourless oil; partial data [α]D25 +18.3 (c, 0.5 in CHCl3); νmax (thin film) 3430 (br, OH), 2101 (sh, N3), 1637 (st, C═O)cm−1; δH (500 Mz, CDCl3) 2.05, 2.09, 2.21 (9H, 3 x s, 3 x CH3), 3.13 (1H, dd, J5,6 4.2 Hz, J6,6′ 13.1 Hz, H-6), 3.46 (1H, dd, J5,6′ 8.2 Hz, H-6′), 4.18 (1H, dd, H-5), 5.34 (1H, dd, J2,3 3.7 Hz, J2,3 10.9 Hz, H-2), 5.49 (1H, d, J3,4 3.0 Hz, H-4), 5.57 (1H, dd, H-3), 5.94 (1H, d, H-1) 7.21 (2H, J=9.3 Hz, 2 x CHCHCNO2), 8.26 (2H, 2 x CHCNO2); 5c (125.7 MHz, CDCl3) 19.9, 20.0, 21.0 (3 x q, 3 x CH3), 51.9 (t, C-6), 53.3 (d, C-2), 66.6 (d, C-3), 67.6 (d, C-4), 69.0 (d, C-5), 95.2 (d, C-1), 115.6, 115.7, 125.3 (3 x s, 3 x C═O), 116.9, 117.0 (2 x d, CHCHCNO2), 126.5, 126.6 (2 x d, CHCNO2), 140.8 (s, CNO2), 167.2, 169.9, 170.2, 171.8 (4 x s, 3 x C═O, 1x CCHCHCNO2); m/z (CI+) 470 (M+NH4+, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:3]=1[CH3:27]
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Tert-Butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (370 mg, 0.93 mmol) was dissolved in DCM (3.0 mL) and cooled to 0° C. TFA (0.50 mL, 6.5 mmol) was then added and the mixture was stirred for 2 h while warming to rt. The mixture was then concentrated and triturated with EtOAc. The slurry was filtered to give 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate. Mass Spectrum (ESI) m/e=298.1 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH:21]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:5]2[N:4]3[CH:21]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 0.5 h

Procedure:
To a mixture of 5.3 parts of 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine prepared in Example 5, 14.8 parts of ethyl orthoformate and 150 parts by volume of ethanol, is added dropwise 4 parts of fconcentrated sulfuric acid under cooling. The whole mixture is stirred for about 30 minutes and neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane, whereby 8-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as crystals. Recrystallization from ethyl acetate yields pale yellow prisms melting at 177° C to 178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>CN(C=O)C.CO>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[N:3][CH:4]=1)[CH3:10]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: CCOc1ccc(Br)nc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(C)=O)cc3)CC2)nc1
Temperature: 180 °C

Procedure:
250 mg (1.24 mmol) 2-Bromo-5-ethoxy-pyridine are added to 250 mg (1.02 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1). The mixture is heated at 180° C. for 1 h. Subsequently the residue is taken up in DMF/methanol and the mixture is purified using reversed phase HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH+0.3% NH4OH) to yield the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH3:13])[CH2:26][CH2:25]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCNc2ccc(F)cc2)CC1

Procedure:
A mixture of 1.9 g of N-(3-chloropropyl)-p-fluoroaniline, 1.9 g of 1-(o-methoxyphenyl)piperazine, 0.5 g of sodium carbonate and 50 ml of dimethylformamide was heated at 80°-90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 1-{3-(p-fluoroanilino)propyl}-4-(o-methoxyphenyl)piperazine, m.p. 79°-80° C; recrystallized from cyclohexane, m.p. 84°-84.5° C.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=C)[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:41]([NH2:44])([CH3:43])[CH3:42]>C1COCC1.ClCCCl>[CH:41]([NH:44][C:26]1[N:25]=[C:24]([O:23][CH:21]2[CH2:22][CH:18]3[CH:19]([C:31](=[O:32])[N:33]([CH3:34])[CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:13][CH:11]4[C:10]([C:8]([NH:7][S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[O:9])([NH:15][C:16]3=[O:17])[CH2:12]4)[CH2:20]2)[CH:29]=[CH:28][N:27]=1)([CH3:43])[CH3:42]
Reactant: CC(C)N
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)Nc1nccc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Compound 10f (30 mg, 0.05 mmol) and isopropylamine (excess) in THF (10 ml) was heated in a microwave oven at 110° C. for 30 min and then left at ambient temperature for 16 hrs. The solvent was stripped of and the residue was redissolved in DCE (15 ml) and degassed with nitrogen. Hoyeda-Grubbs II catalyst (7 mg) was added and the mixture was heated in a microwave oven at 150° C. for 10 min. The mixture was concentrated to dryness and purified by prep. HPLC-MS-UV which gave the pure title compound (3.1 mg), (M+H)+=589.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=O.[C:15]1([NH:21][C:22]([NH2:24])=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25]>CN(C)C=O>[ClH:25].[NH:21]([C:22]1[S:23][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=2)[C:10]#[N:11])[N:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: N#Cc1cc(C(=O)CBr)cc(O)c1O
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2csc(Nc3ccccc3)n2)cc(O)c1O
Reaction time: 5 h

Procedure:
3.8 g of 5-(bromoacetyl)-2,3-dihydroxybenzonitrile dissolved in 25 ml of N,N-dimethylformamide are treated with N-phenylthiourea and stirred at 100° for 5 hours. Thereafter, the solvent is removed by evaporation. The residue is treated with 200 ml of 1N sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 30 g of silica gel with ethyl acetate. The thus-obtained crude product is treated with 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. There is obtained 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzonitrile hydrochloride of m.p. 245°-247°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:21][CH:22]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: Clc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(Cl)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-chlorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.77 min.; [M+H]+: 360.18 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:19])[CH3:18])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:21]N1C(=O)CCC1=O.Cl>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:19])[CH3:18])[CH:12]=2)[C:7]=1[Cl:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-acetyloxy-2-naphthyl)carbamic acid ethyl ester (670 mg, 2.45 mmol), N-chlorosuccinimide (326 mg, 2.45 mmol) and 1 M HCl in acetic acid (2.45 mL, 2.45 mmol) in acetic acid (10 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature the mixture is partitioned between EtOAc and water. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give N-(6-acetyloxy-1-chloro-2-naphthyl)carbamic acid ethyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH2:10][OH:11])[C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:13][C:14]1([CH3:22])[C:16]([CH3:18])([CH3:17])[CH:15]1[C:19](Cl)=[O:20]>>[CH3:13][C:14]1([CH3:22])[C:16]([CH3:18])([CH3:17])[CH:15]1[C:19]([O:11][CH2:10][C:5]1[C:6]([CH3:9])=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[CH3:12])=[O:20]
Reactant: Cc1ccc(C#N)c(C)c1CO
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Product: Cc1ccc(C#N)c(C)c1COC(=O)C1C(C)(C)C1(C)C

Procedure:
In a similar manner, (3-cyano-2,6-dimethylphenyl)methanol is reacted with other 3-(2-halo-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chlorides and others 3-(2,2-dihaloethenyl)-2,2-dimethylcyclopropanecarboxylic acid chlorides, or 2,2,3,3-tetramethylcyclopropanecarboxylic acid chloride to give other (3-cyano-2,6-dimethylphenyl)methyl 3-(2-halo-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylates and 3-(2,2-dihaloethenyl)-2,2-dimethylcyclopropanecarboxylates within the scope of this invention, or (3-cyano-2,6-dimethylphenyl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate, respectively.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:12]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc(N)c1

Procedure:
A mixture of 3.3 g of N-(3-nitrobenzoyl)-N-(2-ethoxy-2-oxoethyl) glycine ethyl ester and 0.5 g of 10% palladium on carbon in 40 ml THF and 40 ml ethyl acetate was stirred in a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to an oil which was purified by HPLC using 50% ethyl acetate-hexane to remove an impurity and ethyl acetate to elute 3.1 g of N-(3-aminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(C(Cl)Cn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
292 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to 1.13 g of methyl 4-mercaptobenzoate in 8 ml of dry dimethylformamide, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. 1.61 g of 1-[2-chloro-2-(4-trifluoromethylphenyl)ethyl]imidazole in 7 ml of dry dimethylformamide was added to this solution and the resulting mixture was heated at 60°-70° C. for 6 hours. At the end of this time, the reaction mixture was treated and purified by the same method as described in Example 1, to give 844 mg of the title compound as an oil.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[CH2:10]2.C(O)C.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH3:20][CH:19]([NH:22][C@@H:2]1[CH2:3][C:4]2[C:9](=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=2[O:14][CH3:15])[CH2:10][C@H:11]1[OH:1])[CH3:21]
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Reactant: CC(C)N
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(C)C)C2

Procedure:
A mixture of 10.3 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene in 50 ml of isopropylamine containing 2.93 ml of absolute ethanol is heated overnight in a small Parr bomb at 105° C ± 5° C (internal pressure = 75-100 psi). The cooled reaction mixture is concentrated in vacuo to 11.51 g of tan solid. Trituration with ether gives 10.1 g of material, melting point 141-144° C. Two recrystallizations from ethyl acetate give 7.0 g of trans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-5,8-dimethoxy-2-dimethoxy-2-naphthalenol, melting point 144°-145° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:4]2[C:11]([C:12]3[CH:13]=[C:14]([CH2:18]O)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:9]([CH2:20][O:21]CC[Si](C)(C)C)[C:5]=2[N:6]=[CH:7][N:8]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([O:33][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]2[C:4]3[C:3]([N:2]([CH3:1])[CH3:28])=[N:8][CH:7]=[N:6][C:5]=3[N:9]([CH2:20][OH:21])[CH:10]=2)[CH:13]=1)=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)c1ncnc2c1c(-c1cccc(CO)c1)cn2COCC[Si](C)(C)C
Product: CN(C)c1ncnc2c1c(-c1cccc(COC(=O)C(F)(F)F)c1)cn2CO

Procedure:
A solution of {3-[4-(dimethylamino)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}methanol (C26) (397 mg, 0.996 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to provide the product (400 mg) as a brown oil. This material was taken directly into the following step. LCMS m/z 395.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=[O:20])[C:14](OCC)=[O:15])=[N:8][C:7]=2[CH:24]=1.[OH-:25].[Na+]>C(O)C>[SH:10][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][C:7]=1[N:8]1[C:14](=[O:15])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][NH:11][C:9]1=[O:25]
Reactant: [OH-]
Reactant: CCOC(=O)C(=CNc1nc2cc(OC)ccc2s1)C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S)c(-n2c(=O)[nH]cc(C(=O)O)c2=O)c1

Procedure:
Diethyl N-(5methoxybenzthiazole-2-yl)-aminomethylene-malonate is, as described in Example 1A, Variant II, heated in a mixture of 10% aqueous sodium hydroxide solution and ethanol. Without isolating the 1-(2-mercapto-5-methoxyphenyl)-5-carboxypyrimidine-2,6-dione formed as intermediate, the reaction mixture is strongly acidified, 8-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid thereby precipitating out. The precipitate is subsequently stirred for about 1 hour in the acidic medium. After isolation and drying, the product has a melting point of 277°-278° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[C:28]([CH3:35])[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:34])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
HATU (440 mg, 1.16 mmol) was added to a solution of 6-fluoro-4-methyl-3-pyridinecarboxylic acid (supplied by Frontier Scientific) (150 mg, 0.97 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.422 ml, 2.42 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (358 mg, 1.16 mmol) was added and stirring was continued for 1.25 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in hexanes, gave the title compound (432 mg) as a yellow gum.