Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCSc1ccc(F)cc1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Part A: A solution of 10 g (78 mmol) of 4-fluorothiophenol and 8 g (86 mM) of 3-chloro-1-propanol in 80 mL of anhydrous DMF was purged with nitrogen for 20 min., then treated with 32 g (234 mM) of potassium carbonate. After one hour, the reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine (3×), dried (MgSO4), and concentrated to afford 16 g of crude product. The crude product was chromatographed on silica gel using 30-45% ethyl acetate/hexane to yield 12 g of pure 3-[(4-fluorophenyl)thio]propan-1-ol, m/z=203 (M+NH4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([CH3:9])=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nnc2n1CCNC2
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1CCN(c1cccc(Br)n1)C2
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 2,6-dibromopyridine (434 mg, 1.832 mmol, Aldrich), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (380 mg, 2.75 mmol, MolBridge) and potassium carbonate (253 mg, 1.832 mmol) in dioxane (1.8 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 4 h. The reaction was cooled to RT, H2O was added and the resulting precipitate was collected by filtration, washed with H2O and dried to give the crude product. MS (ESI, pos. ion) m/z: 294 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Product: Cc1nc2cc(Cl)ccc2n1-c1ccccc1
Yield: 56 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Chloro-1-bromo-2-nitrobenzene (118 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol), as starting materials to yield the title compound as yellow solid (68 mg, 56% yield). mp 109-111° C. 1H NMR (DMSO) δ 2.52 (s, 3 H), 7.22 (d, J=8.6 Hz, 1 H), 7.34 (d, J=8.6 Hz, 1 H), 7.48-7.59 (m, 5 H), 7.86 (s, 1 H); 13C NMR δ 13.5, 112.2, 116.4, 123.9, 126.9, 127.9, 129.7, 130.1, 133.9, 138.5, 154.0, 157.0. HRMS (FAB): cal. for C14H12N2Cl [M+H+]: 243.0689; found: 243.0684.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.CN(C)CC(O)=O>[Cu]I.CN(C=O)C.O1CCOCC1>[CH:18]1([C:10]2[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]3=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:29][C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Reactant: Oc1ccc(F)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(Oc4ccc(F)cc4)cc3)c12

Procedure:
A mixture of 1-(4-bromo-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine (30.0 mg, 0.0874 mmol), 4-fluorophenol (29.4 mg, 0.262 mmol), copper(I) iodide (5 mg, 0.03 mmol), Cs2CO3 (114 mg, 0.350 mmol), N,N-dimethylglycine hydrochloride (10 mg, 0.08 mmol) and 5:1 dioxane:DMF (1 mL) was microwaved at 120° C. for 4 h (CEM; PowerMAX). The mixture was filtered through a syringe filter pad to remove any solid particles, then concentrated in vacuo. DMF (1 mL) was added to bring the mixture to a homogeneous solution, and Gilson HPLC was used to purify. The fractions containing the product were passed through a benzene-sulfonic acid SPE cartridge, washed with MeOH (10 mL), and flushed out using 2M NH3 in MeOH. The material was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.99-2.09 (m, 1H), 2.11-2.24 (m, 1H), 2.45-2.55 (m, 2H), 2.58-2.69 (m, 2H), 3.77-3.87 (m, 1H), 5.12 (br. s., 2H), 7.01-7.13 (m, 8H), 7.61-7.65 (m, 2H). MS (ES+): m/z 374.98 (100) [MH+]. HPLC: tR=2.55 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol), N,N-dimethylglycine (19 mg, 0.18 mmol), EDCl (36 mg, 0.19 mmol), HOBt (26 mg, 0.19 mmol), and N,N-diisopropylethylamine (90 μL, 0.52 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 20 mg (20%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.37 (s, 1 H), 8.09 (s, 1 H), 7.82 (d, 1 H), 7.67 (s, 1 H), 7.26-7.39 (m, 5H), 7.16-7.23 (m, 2 H), 5.66 (s, 2 H), 4.40 (d, 1 H), 4.10 (d, 1 H), 3.01-3.23 (m, 3 H), 2.75 (t, 1 H), 2.18 (s, 6H), 2.06-2.15 (m, 3 H), 1.70 (q, 1 H), 1.53 (q, 1 H); ES-MS m/z 592.16 HPLC RT (min) 2.39.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[N:14]1([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[S:27])=[CH:21][C:20]=2[O:29][CH3:30])[CH:18]=[CH:17][N:16]=[CH:15]1>>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([C:3]2[N:28]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([N:14]4[CH:18]=[CH:17][N:16]=[CH:15]4)=[C:20]([O:29][CH3:30])[CH:21]=3)[S:27][CH:2]=2)[CH:10]=1
Reactant: COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1cc(NC(N)=S)ccc1-n1ccnc1
Product: COc1ccc(Br)cc1-c1csc(Nc2ccc(-n3ccnc3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 232 mg (0.75 mmol) 2-bromo-1-(5-bromo-2-methoxyphenyl)ethanone and 170 mg (0.68 mmol) (4-imidazol-1-yl-3-methoxy-phenyl)-thiourea yielding 130 mg (41%) [4-(5-bromo-2-methoxy-phenyl)-thiazol-2-yl]-(4-imidazol-1-yl-3-methoxy-phenyl)-amine as a light yellow solid. MS ISP (m/e): 457.1/459.3 (100/90) (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:2]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[O:7])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1cccs1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1
Yield: 50 %

Procedure:
A mixture of 2-thienyl-(4-hydroxy-phenyl)ketone (M.p. 112° C.; 65 g), ethyl bromoisobutyrate (62 g) and potassium carbonate (88 g) in 2-butanone (500 ml) is refluxed for 24 hours. After removing the solid by filtration in the hot, the solvent is removed. The unreacted phenol is extracted from the residue with an alkaline aqueous solution. The usual treatments give, in a yield of 50%, the ester which melts at 45° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[O:23]C(=O)C)[C@H:15]2[C@H:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:27][CH3:28])=[CH:11][C:12]=1[CH2:13][CH2:14]2)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@H:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:27][CH3:28])=[CH:11][C:12]=1[CH2:13][CH2:14]2
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](OC(C)=O)C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
A solution of the diacetate (25) (25 mg, 0.065 mmol) in dry ether (1 ml) was added to a stirred solution of lithium aluminium hydride (5 mg, 0.13 mmol) in dry ether (2 ml) at 0° C. under argon. After 15 min, excess lithium aluminium hydride was destroyed by addition of wet ether and then dropwise addition of water. The ethereal layer was separated, dried, and evaporated, and the residue was chromatographed on silica (1 g) to give the product (6) (18 mg, 91%), m.p. 161°-2° C. (from ether-light petroleum), νmax 3420 cm-1 (OH), δ (250 MHz), 7.21 (1 H, d, J 8 Hz, 1-proton), 6.76 (1 H, dd, J 8 and 2.5 Hz, 2-proton), 6.67 (1 H, d, J 2.5 Hz, 4-proton), 4.74 (1 H, m, 11-proton), 3.78 (3 H, s, OCH3), 3.71 (1 H, m, 17-proton), 2.86 (2 H, m, 7-protons), 2.44 (1 H, dd, J 11 and 2 Hz, 9-proton), 2.28 (1 H, dd, J 14 and 2.5 Hz, 12-proton), 2.11 (1 H, qt, J 11, 9, 2.5, and 2 Hz, 8-proton), 1.98-1.31 (7 H, m), 1.61 (2 H, br s OH), 1.03 (3 H, s, 18-CH3);
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:4]2[C:9]([OH:10])=[N:8][CH:7]=[N:6][C:5]=2[S:11][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2c(O)ncnc2s1
Solvent: CC(=O)O
Product: Cc1sc2ncnc(O)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 6-methylthieno[2,3-d]pyrimidin-4-ol (95 mg, 0.57 mmol, 1.00 equiv) in acetic acid (2 mL) was added Br2 (181 mg, 1.13 mmol, 2.00 equiv) and the resulting solution was stirred overnight at room temperature under nitrogen. After finished of the reaction, the reaction was then quenched with saturated aqueous NaHSO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the resulted 5-bromo-6-methylthieno[2,3-d]pyrimidin-4-ol (111 mg, 79%) as a yellow solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([NH:26][C:27](=[O:54])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C@@H:42]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@@H:43]([CH3:46])[CH2:44][OH:45])[C:36]3=[O:53])[CH:29]=2)[CH2:25][CH2:24]1>ClCCl>[CH:23]1([NH:26][C:27](=[O:54])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C@@H:42]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@@H:43]([CH3:46])[CH:44]=[O:45])[C:36]3=[O:53])[CH:29]=2)[CH2:24][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CO)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
A solution of Dess-Martin periodinane (600 mg) in dichloromethane (3 mL) was added dropwise to a solution of N-cyclopropyl-3-(3-((1R,2R)-3-hydroxy-2-methyl-1-phenylpropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 136, 405 mg) in dichloromethane (4 mL) at 25° C. The resulting mixture was stirred at 25° C. for 30 minutes. The reaction mixture was quenched with sat. aqueous Na2S2O3 (7 mL) and sat. aqueous NaHCO3. The mixture was stirred for 15 min. and extracted into dichloromethane. The organic phase was dried (Na2SO4), filtered and evaporated to afford crude product (475 mg) that was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.[CH2:20](Br)[CH:21]=[CH2:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:17]1[CH2:18][CH2:19][N:14]([C:2](=[O:1])[CH2:3][N:4]2[C:8](=[O:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[S:5]2)[CH2:15][CH2:16]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1CCN(C(=O)Cn2sc3ccccc3c2=O)CC1

Procedure:
Compound 10 (30 mg, 0.11 mmol) was treated with allyl bromide (16 mg, 0.13 mmol) and DIEA (40 mg, 0.31 mmol) in anhydrous CH2Cl2 (2 mL) at room temperature for 6 h. Allyl bromide then was removed by reduced pressure and the residue was washed by H2O to give the title compound after purification on a thin-layer silica-gel plate (20 cm×20 cm×2 mm) using CH2Cl2/MeOH (9:1) as the developing solution. C16H19N3O2S; white solid; mp 119-120° C.; IR vmax (neat) 3072, 2920, 2857, 2801, 1717, 1653, 1448, 1339, 1262, 1234, 1136, 1038, 1000, 924, 748 cm−1, 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J=8.0 Hz), 7.58 (1H, t, J=7.6 Hz), 7.53 (1H, d, J=8.0 Hz), 7.37 (1H, t, J=7.6 Hz), 5.80 (1H, m), 5.16 (2H, m), 4.69 (2H, s), 3.65 (2H, t, J=5.2 Hz), 3.57 (2H, t, J=5.2 Hz), 2.99 (2H, d, J=6.8 Hz), 2.45 (4H, m); 13C NMR (100 MHz, CDCl3) δ 165.5, 164.7, 134.1, 132.0, 126.7, 125.3, 120.2, 118.5, 61.5, 52.9, 52.5, 45.3, 44.8 (2×), 42.2, 29.8; ESI-HRMS calcd for C16H20N3O2S: 318.1274. found: m/z 318.1274 [M+H]+.
Reaction SMILES: C(O[CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=1[OH:20])(=O)C.[H-].[Ca+2].[H-].[Cl-].[NH4+]>CS(C)=O>[CH3:21][C@@:7]1([CH:6]=[CH2:5])[CH2:8][CH2:9][C:10]2[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=2[O:20]1
Reactant: CC(=O)OC/C=C(\C)CCc1c(C)c(O)c(C)c(C)c1O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: C=C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A solution of 106 mg (0.36 mmol) of (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate and 9 mg (3%) of [[(R)-6,6'-dimethyl-1,1'-biphenyl-2,2'-bis(diphenylphosphine)]-P,P'][(η-3)-2-propenyl]palladium perchlorate in 2 ml of DMSO was treated with 15 mg of calcium hydride and stirred at room temperature for three days. Thereafter, the mixture was poured into saturated ammonium chloride solution and extracted with ether. The combined extracts were washed with water and dried. The residue remaining after removal of the solvent was purified as described in Experiment 1, yielding 56 mg of (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-vinyl-2H-[1]-benzopyran-6-ol. O.P. 33%.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][C:20]=1[F:45])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+]>C(O)C>[F:37][C:33]1[CH:34]=[C:35]([F:36])[C:27]2[O:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:9](=[O:18])[C:10]5=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]5[C:12]4=[O:13])=[C:20]([F:45])[CH:21]=3)=[CH:30][C:29](=[O:31])[C:28]=2[C:32]=1[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN4C(=O)c5ccccc5C4=O)C(C)=O)c(F)c3)cc(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Yield: 33.8 %

Procedure:
200 mg of Compound 31 was dissolved in 4 ml of ethanol, 2 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled on ice and adjusted to pH 8 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration and subjected to preparative thin layer chromatography (chloroform:acetone=20:1) to give 63 mg (34%) of Compound 32.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[Cl:14][C:15]1[C:16]([CH2:25][CH:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH3:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:14][C:15]1[C:16]([CH2:25][CH:26]([N:28]([CH:29]2[CH2:31][CH2:30]2)[C:8]([C:7]2[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=2[F:11])=[O:9])[CH3:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(Cc1ncc(C(F)(F)F)cc1Cl)NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cc1ncc(C(F)(F)F)cc1Cl)N(C(=O)c1c(C(F)F)nn(C)c1F)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.9 %

Procedure:
At ambient temperature, a solution of 74 mg (0.35 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 2 ml of tetrahydrofurane is added dropwise to a solution of 100 mg (0.317 mmol) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}cyclopropanamine and 0.137 ml (0.984 mmol) of triethylamine in 3 ml of tetrahydrofurane. The reaction mixture is stirred for 15 hrs at ambient temperature. The solvent is removed under vacuum and 50 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×25 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried over magnesium sulfate to yield after concentration 131 mg of an oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 72 mg (47% yield) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a colorless oil (M+H=455).
Reaction SMILES: OS(O)(=O)=O.C(=O)=O.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:9]([C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated H2SO4 (1 L) was cooled to −10° C. with a dry ice IpOH bath in a 2 L 3-neck round bottom flask fitted with a mechanical stirrer and temperature probe. 2-t-Butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized at −10° C., KNO3 (101 g, 1001 mmol) was added portion-wise, as the solid, over 4 h, maintaining the temperature between −20 and −5° C. Once all of the KNO3 was added, the reaction was stirred overnight with gradual warming to RT. The reaction was quenched by diluting with H2O and extracting 3× with EtOAc. The EtOAc extracts were washed multiple times with saturated NaHCO3(aq), until gas evolution ceased, then with brine. The EtOAc extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving a black oil. The oil was eluted through a 36×7 cm column of silica gel with a 5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step) giving 2-tert-butyl-5-nitro-phenylamine as a red solid.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:28]([C@@H:25]2[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCN(Cc3ccccc3)CC2)C1

Procedure:
4.99 g (21.5 mmol) of benzylbis(2-chloroethyl)amine hydrochloride (XX) were dissolved in ethanol (120 ml) and, while stirring, 4.00 g (21.5 mmol) of (R)-(+)-N-Boc-3-aminopyrrolidine and 7.22 g (85.9 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 4.48 g (60%) of yellow solid
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1)=[O:7].[BrH:19]>O>[BrH:19].[NH:11]1[CH2:12][CH2:13][CH:8]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(C(=O)c2cccs2)CC1
Agent: Br
Solvent: O
Product: O=C(c1cccs1)C1CCNCC1
Yield: 85 %

Procedure:
A mixture of 20 parts of ethyl 4-(2-thienylcarbonyl)-1-piperidine-carboxylate and 120 parts of hydrobromic acid solution 48% in water is stirred and refluxed for 2 hours. The reaction mixture is cooled and the precipitated product is filtered off. It is washed with 2-propanol and dried, yielding 17 parts (85%) of (4-piperidinyl)(2-thienyl)methanone hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2ccccc2cc1C(=O)O
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2ccccc2cc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.2 g. of 3-methoxy-2-naphthoic acid, 5.2 g. of aminotetrazole, and 80 ml. of pyridine was added dropwise 6.4 ml. of thionyl chloride, maintaining the temperature below 70° C. After stirring for one hour, the mixture was cooled to 25° C. and evaporated to dryness. The residue was washed with dilute hydrochloric acid, then recrystallized from N,N-dimethylformamide, then dissolved in base, filtered, reprecipitated with dilute acid, filtered, washed with methanol, then recrystallized again from N,N-dimethylformamide to provide 3-methoxy-N-(tetrazol-5-yl)naphthalene-2-carboxamide (a type IV compound), m.p. 280°-283° C.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]([O:16]CC)=[O:15])[NH:3][C:4](=[O:12])[NH:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.O.[OH-].[Li+]>>[CH3:1][N:2]([CH2:13][C:14]([OH:16])=[O:15])[NH:3][C:4](=[O:12])[NH:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN(C)NC(=O)NCc1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)NC(=O)NCc1cccs1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-2 with the modification that the reaction was carried out for 2 hours, ethyl 2-(1-methyl-2-(thiophen-2-ylmethylcarbamoyl)hydrazinyl)acetate (Compound V-13) 1.38 g (5.1 mmol) was reacted with lithium hydroxide monohydrate 426 mg (10.1 mmol) to obtain the title compound 1.0 g (82%).