Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[NH:20][C:19](=[O:28])[C@@H:18]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][C:16]2=[CH:40][CH:41]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([NH:29][C@H:18]2[CH2:17][C:16]3=[CH:40][CH:41]=[C:13]([CH:14]=[CH:15]3)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:26])[CH3:27])[NH:20][C:19]2=[O:28])(=[O:31])=[O:32])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCCCSC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 57 (47 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.42 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 9 mg, 20%. Rf=0.45 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].CC(C)([O-])C.[K+]>C1COCC1>[CH:12]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:2]2[C:7]([CH:8]3[CH2:10][CH2:9]3)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc(Cl)c1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Cl)c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 4,6-dichloro-5-cyclopropyl-pyrimidine (700 mg, 3.70 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (636.6 mg, 3.70 mmol) in dry THF under nitrogen at 0° C., potassium tert-butoxide (1M solution in THF, 4.45 mL) was added dropwise. The reaction was stirred at rt for 30 min. The mixture was quenched with water and extracted with EtOAc (3×). The organic layer was washed with water, sat. NH4Cl and brine, followed by drying over sodium sulfate and concentration under vacuo. The resulting oil was purified by flash chromatography (0-20% EtOAc/Hexanes) to afford 4-(6-chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (0.927 g, 73.7%) as colorless oil. Exact mass calculated for C16H22ClN3O3 339.13, found 340.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH:14](=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1cccc(F)c1F

Procedure:
Butyllithium (2.5 M in hexanes 52.5 ml, 0.131 mol) was added dropwise to a stirred, cooled (−78° C.) solution of difluorobenzene (12.0 g, 0.105 mol) in dry THF (400 ml) under a stream of dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and a solution of nonanal (14.9 g, 0.105 mol) in dry THF (50 ml) was added dropwise at −78° C. The mixture was allowed to slowly reach room temperature overnight. Ammonium chloride solution (2M, 200 ml) was added and the product was extracted into ether (2×150 ml), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo and the residue was distilled under reduced pressure to give a colourless oil.
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([OH:11])([CH2:10][C:4]([C:13]([OH:15])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16](O)[CH2:17][CH2:18][CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([OH:1])([CH2:3][C:4]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CCCCO
Reactant: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
A mixture of 300 mmole of the above-prepared 3,5-dihydroxy-1-adamantanecarboxylic acid, 450 mmole of n-butanol, 15 mmole of sulfuric acid, and 900 ml of toluene was stirred under reflux of toluene for 5 hours. The reaction mixture was concentrated and was then subjected to column chromatography on a silica gel to yield n-butyl 3,5-dihydroxy-adamantanecarboxylate.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35]>>[CH3:36][C:31]1[C:30]([CH2:29][N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1noc(C)c1CCl
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(C)c1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-(chloromethyl)-3,5-dimethylisoxazol, to give the desired product as a white solid (66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:30])[CH3:9])=[CH:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.316 min, m/z=524.1; 1H NMR (CDCl3) 1.28-1.38 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H), 1.81-1.98 (m, 2H), 2.13 (m, 1H), 2.24 (m, 2H), 2.83 (m, 4H), 3.01 (m, 2H), 3.91 (s, 3H), 4.15 (m, 1H), 5.62 (m, 1H), 6.73 (d, 1H), 6.91 (d, 2H), 7.18-7.32 (m, 7H), 7.62 (dd, 1H), 8.21 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (79 mg, 87%), MS (ISP) m/z=365.5 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([CH2:23][O:24][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:15]=1)=[O:10])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[C:25]12([O:24][CH2:23][C:12]3[C:11]([C:9]([OH:10])=[O:8])=[CH:15][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: Cc1ccccc1-n1cc(C(=O)OCc2ccccc2)c(COC23CC4CC(CC(C4)C2)C3)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-n1cc(C(=O)O)c(COC23CC4CC(CC(C4)C2)C3)n1

Procedure:
A solution of 3-(adamantan-1-yloxymethyl)-1-o-tolyl-1H-pyrazole-4-carboxylic acid benzyl ester (0.359 g, 0.79 mmol) in MeOH-THF (1:1/24 mL) was hydrogenated over 10% palladium on charcoal (50 mg) for 19 h. The reaction mixture was filtered through a pad of Celite and the filtrate evaporated to afford the product, (0.29 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:17][CH3:18])[C:13]=1[CH:14]([CH3:16])[CH3:15])[CH2:6]P(=O)([O-])[O-].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([CH:14]([CH3:16])[CH3:15])=[C:12]([O:17][CH3:18])[CH:11]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COc1cc(CP(=O)([O-])[O-])cc(OC)c1C(C)C
Reactant: O=Cc1cc(F)cc(F)c1
Product: COc1cc(C=Cc2cc(F)cc(F)c2)cc(OC)c1C(C)C
Yield: 27 %

Procedure:
This material was prepared from (3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3,5-difluorobenzaldehyde in 27% yield in the same way as described in example 21. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.66 (qint., J=7.0 Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8-7.2 (m, 5H).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:13]([S:24][CH2:25][C@@H:26]([C:35](O)=[O:36])[NH:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>CCOC(C)=O>[CH3:31][C:30]([CH3:32])([CH3:33])[C:29]([O:28][NH:27][C@@H:26]1[C:35](=[O:36])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]=2[S:24][CH2:25]1)=[O:34]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1c(N)cccc1-c1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)ON[C@H]1CSc2c(cccc2-c2ccccc2)NC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
0.269 mL of diethyl cyanophosphonate (289.4 mg, 1.774 mmol) are placed in a 25 mL three-necked flask containing 580 mg of 39 (1.493 mmol) and 7 mL of DMF, at 0° C., followed, 10 minutes later, by addition of 0.201 mL of TEA (1.43 mmol). The reaction medium is stirred at 0° C. for 2 hours. 20 mL of EtOAc are added and the mixture is then washed with twice 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product (600 mg of yellow oil) is chromatographed on a silica cartridge (30 g) with a heptane/EtOAc eluent (as an EtOAc gradient: 10% to 50%). 410 mg of expected product 40 are obtained (white solid).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:31]([C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([C:7]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:43][S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=4)(=[O:42])=[O:41])=[O:21])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A suspension of EXAMPLE 1D (39.8 mg, 0.05 mmol), 3-nitrobenzenesulfonamide (20.2 mg, 0.05 mmol), 4-dimethylaminopyridine (24.4 mg, 0.1 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38.4 mg, 0.1 mmol) in dichloromethane (3 ml) was stirred for 16 hours at room temperature. The reaction mixture was concentrated and purified by RP HPLC (Zorbax SB-C8, gradient 30% to 100% CH3CN/water/0.1% TFA). 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 10.49 (br s, 1H), 8.68 (s, 1H), 8.43-8.52 (m, 1H), 8.36 (d, 1H), 7.90 (t, 1H), 7.79 (d, 2H), 7.47 (t, 2H), 7.43 (t, 1H), 7.32-7.40 (m, 3H), 7.27 (d, 2H), 7.18 (d, 2H), 6.99 (d, 2H), 6.26 (t, 1H), 3.84 (d, 2H), 3.38-3.54 (br s, 4H), 3.32 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10](OC)=[O:11]>C1(C)C=CC=CC=1>[CH2:14]([C:8]1[CH:9]=[C:10]([OH:11])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: Nc1cc[nH]n1
Solvent: Cc1ccccc1
Product: CCCCc1cc(O)n2nccc2n1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A suspension of 100 g of 3-aminopyrazole and 190 g of methyl 3-oxoheptanoate in 120 ml of toluene was heated under reflux at 100° C. for 3 hours and cooled. Toluene was distilled off under reduced pressure, and diethyl ether was added to the residue. The crystals precipitated were collected and sequentially washed with diethyl ether and acetonitrile to provide 184 g of 5-n-butyl-7-hydroxypyrazolo[1,5-a]pyrimidine as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1 below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)sc2c1
Yield: 86.3 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.06 g, 0.23 mmol) and 3-trifluoromethylbenzoyl chloride (0.054 g, 0.26 mmol) in dry pyridine (7.5 ml) to give the title compound (0.085 g, 85%) as a colourless solid after work-up.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([O:24][CH2:16][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 5-(4-Bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl alcohol. After the reaction the material was submitted to chiral preparatory HPLC (Chiralcel AS Column, 2% EtOH in hexanes, 65 minute run). The first enantiomer off of the column is Enantiomer A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:3]=1.[CH:15](=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:8]([C:7]1[C:2]([NH:1][CH2:15][CH3:16])=[N:3][C:4]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: CC=O
Reactant: COC(OC)c1ccc(C#N)c(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1nc(C(OC)OC)ccc1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
2-Amino-3-cyano-6-dimethoxymethylpyridine (39.6 g, 0.2 mol) and 12 ml (0.2 mol) of acetaldehyde were dissolved in 400 ml of acetic acid, and the resulting solution was mixed with 45.5 g (0.2 mol) of sodium triacetoxyborohydride and stirred for 2.5 hours at room temperature. The reaction solution was concentrated under a reduced pressure, diluted with chloroform and then washed with 1 N sodium hydroxide aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 33.9 g of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine as an oily material. The yield was 77%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8](Cl)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
(2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-carbamic acid ethyl ester (300 mg, 0.96 mmol) was dissolved in 10 mL of tetrahydrofuran and benzylamine (0.103 mL, 0.96 mmol) was added followed by triethylamine (0.194 mL, 1.91 mmol) and the reaction mixture was stirred at 60° C. overnight. The solvent was removed and the solid was partitioned in ethyl acetate/water (50 mL/30 mL), the organic layer was dried over MgSO4, concentrated and purified by column chromatography on silica eluting with a gradient of 0% to 10% of methanol in ethyl acetate in to give 323 mg of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[C:2]=2[F:1])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2F)cn1
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1F)C1CCCCC1)OC

Procedure:
The subtitled compound (1.6 g) was prepared form 3-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 16, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.46 (td, J=2.0 and 7.6 Hz, 1H), 7.15-7.02 (m, 2H), 4.53 and 4.37 (2×t, J=5.4 Hz, 1H), 4.04-3.94 and 3.70-3.60 (2×m, 1H), 3.92 (s, 3H), 3.76-3.64 (m, 4H), 3.35 and 3.33 (2×s, 6H), 3.36-3.26 (m, 2H), 2.95-2.88 (m, 2H), 2.65 and 2.63 (2×t, J=6.3 Hz, 2H), 1.81-1.00 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH2:45]C)[CH2:43]C>O1CCOCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:45])[CH2:41][CH2:40][CH2:39][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(N)cc4)c3)c2)n(C)n1
Reactant: CCN(CC)CCCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(NCCCN(C)C)cc4)c3)c2)n(C)n1
Temperature: 100 °C
Yield: 4 %

Procedure:
N-[(4-{amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treated with (3-Chloro-propyl)-diethyl-amine (0.047 g, 0.252 mmol) and TEA (0.070 mL, 0.504 mmol). The reaction mixture was then heated to 100° C. for 48 h then cooled to room temperature. The cooled mixture was dissolved in EtOAc (5 mL) and then extracted with water (3×5 mL) and with brine (5 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to give the title compound (4 mg, 3.5%).
Reaction SMILES: [OH:1]C1C=CC(C2C=CC(O)=CC=2)=CC=1.C(O)(=O)CCCC[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[OH:1][C:22]1[CH:21]=[CH:20][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Product: O=C(O)c1ccc(O)cc1

Procedure:
Polymerization was carried out in the same way as Example 1, except that (A) preparing materials were changed to 4,4′-dihydroxybiphenyl, dodecanedioic acid, 4-hydroxybenzoic acid, acetic anhydride, and (B) a mixture of 4,4′-dihydroxybiphenyl, dodecanedioic acid, 4-hydroxybenzoic acid, acetic anhydride at a molar ratio of 1.05:1:2:4.1 in which 4,4′-dihydroxybiphenyl was excess by 5 mol % was prepared in a reactor vessel, thereby producing a thermoplastic resin in which 4-hydroxybenzoic acid was copolymerized with the resin of Example 1. A molecular structure, sealed end groups, and a sealing rate of ends are shown in Table 2, and changes in number average molecular mass and thermal conductivity before and after melting are shown in Table 3.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13](C(=O)C)[CH3:14])=[CH:6][C:5]=1[O:18][CH3:19].[OH-].[Na+]>C(O)C>[CH3:19][O:18][C:5]1[CH:6]=[C:7]([NH:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:20])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 547b from 4-(Acetyl-methyl-amino)-2-methoxy-5-nitro-benzoic acid methyl ester and NaOH in ethanol.