Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[CH:24]3[CH:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)[C:18]2=[O:27])[CH2:9][CH2:8]1.[NH3:29]>>[O:27]=[C:18]1[CH:19]2[CH:24]([CH:23]=[CH:22][CH:21]=[CH:20]2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:29])=[O:2])[CH2:8][CH2:9]1
Reactant: N
Reactant: COC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Product: NC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Temperature: 70 °C
Yield: 40 %

Procedure:
A solution containing 7.0 M methanolic ammonia (50 mL) and compound 3 (0.90 g, 2.33 mmol) was heated in a sealed tube at 70° C. for 72 hours. The solution was then cooled to ambient temperature, and concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-3% methanol in dichloromethane to afford the desired product 4 (0.5 g, 40%) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.25 (m, 3H), 1.55 (m, 2H), 1.62-1.80 (m, 4H), 1.90 (m, 2H), 2.18 (t, 2H), 2.34 (t, 2H), 2.90 (d, 2H) 3.68 (s, 3H), 5.40 (br, 2H), 7.68 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]([NH:21][CH2:22][CH2:23]CCCCN)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:29]1(N)C(F)=C(F)C(F)=[C:31]([NH2:38])[C:30]=1F.[ClH:41].Cl>>[ClH:41].[ClH:41].[NH2:38][CH2:31][CH2:30][CH2:29][CH2:23][CH2:22][NH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(NCCCCCCN)CC[C@@H]12
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCCCN)CC[C@@H]12

Procedure:
N-(3-methoxy-1,3,5(10)-estratrien-17-yl)-1,6-hexanediamine and the corresponding dihydrochloride salt;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:11]4)[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 27 Step 2, 418 mg, 1.33 mmol) and 2-oxopropanethioamide (Intermediate 2, 412 mg, 3.99 mmol) were dissolved in dry MeOH (6 mL) and the resulting solution was heated at 60° C. under N2(g) overnight. The reaction mixture was allowed to cool to r.t. A precipitate formed which was filtered off and dried in vacuo, yielding the title compound (387 mg, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29-1.47 (m, 2H), 1.49-1.62 (m, 2H), 1.81-2.08 (m, 4H), 2.28 (s, 3H), 3.09 (d, 1H), 3.15 (d, 1H), 7.02 (d, 1H), 7.33 (d, 1H), 7.53 (d, 1H), 12.42 (s, 1H); MS (ES+) m/z 399.0 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[NH:10][N:9]=[C:8]([NH2:11])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][CH:13]([CH:16]=O)[CH:14]=O>>[Br:12][C:13]1[CH:14]=[N:11][C:8]2[N:9]([N:10]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=2)[CH:16]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1n[nH]c(N2CCCC2)n1
Product: Brc1cnc2nc(N3CCCC3)nn2c1

Procedure:
The title compound, a light red solid, MS: m/e=268.1/270.1 (M+H+), can be prepared in accordance with the general method of example 42, step 1 from 5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylamine (CAS 154956-89-5) and 2-bromomalonaldehyde.
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[C:3]#[C:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:1][CH:2]([CH2:10][CH3:11])[C:3]#[C:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: CCC(O)C#CCC(=O)OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C#CCC(=O)OC)OC(C)=O
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A solution of 355 mg (2.5 mmol) of methyl 4-hydroxyhex-2-ynecarboxylate (cf. J. Kunes et al., Coll. Czech. Chem. Comm. 66, 1809-1830, 2001) and 243 μl (3 mmol) of pyridine in 25 ml of dichloromethane is slowly admixed at 0° C. with 196 μl (3 mmol) of acetyl chloride. After 16 h at room temperature, the mixture is washed successively with dilute aqueous sulphuric acid and sodium hydrogencarbonate solution. Drying over magnesium sulphate and concentrating the organic phase affords 410 mg (89% of theory) of methyl 4-acetoxyhex-2-ynecarboxylate.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)CCC.[Cl-].[Li+]>C1(C)C=CC=CC=1.[Pd]>[CH2:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCc1nc2ccccn2c1Br
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccccn2c1-c1ccncc1
Yield: 38.7 %

Procedure:
To a solution of 3-bromo-2-ethyl-imidazo[1,2-a]pyridine (1.4 g, 6.28 mmol), 4-tributyistannylpyridine (2.31 g, 6.28 mmol) and Pd (II) (Ph3P)2Cl2 (442 mg, 0.63 mmol) in toluene (5 mL) was added lithium chloride (26.7 mg, 0.63). After refluxing for 18 h, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). Combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 100% ethyl acetate, then 10% methanol in methylene chloride afforded the title compound (543 mg) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 89.3 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 162 mg, 0.58 mmol) in THF. 250 mg (90%) of title compound (95) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1CCCN1Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCCC5C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the title compound (16%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH2:26][OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>ClCCl>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH:26]=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOc1cc(I)ccc1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCOc1cc(I)ccc1C=O
Temperature: 25 °C

Procedure:
A solution of dimethyl sulfoxide (3 ml, 41.4 mmol) in dichloromethane is added to a solution of oxalyl chloride (20.7 mmol, 1.8 ml) in dichloromethane (55 ml). A solution of (2-heptyloxy-4-iodophenyl)methanol (6.55 g, 18.8 mmol) in 25 ml of dichloromethane is added dropwise to the solution previously obtained, at −78° C. The mixture is stirred until the temperature returns to room temperature. The organic phase is acidified with a 2N hydrochloric acid solution. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. 6.5 g (100%) of the expected compound are recovered in the form of a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1>CN(C)C=O>[C:52]([O:51][C:49]([N:46]1[CH2:45][CH2:44][CH:43]([NH:42][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:48][CH2:47]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a mixture of 0.25 g (0.56 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.30 mL (1.7 mmole) of ethyldiisopropyl amine and 0.12 g (0.62 mmole) of 4-amino-1-Boc-piperidine in 4.0 mL of dimethylformamide was added 0.27 g (0.62 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with hexane-ethylacetate (gradient, 70:30-0:100) gave 0.21 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-71) as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 0.713 ml (6.0 mmol) of benzyl bromide in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1→2:1) and crystallisation from ether/hexane yields the pure title compound: TLC Rf (D)=0.36.
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13].[N+](C1NC2C=CC=CC=2N=1)([O-])=O>C(O)(=O)C(C)C.CCOC(C)=O.[Pd]>[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CC(C)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1nc2ccc(N)cc2[nH]1
Reaction time: 12 h
Yield: 92 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of isobutyric acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a dark brown residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo, yielding an oil which was characterized as 2-isopropyl-5-nitrobenzimidazole and subjected to a following reaction without further purification. The nitrobenzimidazole and 50 mg of 10% Pd—C were dissolved in 100 ml of MeOR and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][NH:4]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:28][C:25]([F:26])([F:27])[C:24]([C:21]1[CH:22]=[N:23][C:18]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:11])=[O:10])[CH2:8][C@@H:3]2[CH3:2])=[N:19][CH:20]=1)([OH:33])[C:29]([F:32])([F:31])[F:30]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 85 °C

Procedure:
A 20-mL vial was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (0.75 g, 2.6 mmol, Example 27), (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.92 g, 3.3 mmol, Intermediate D), 15 mL of dioxane, and Hünig's base (1.2 mL, 6.6 mmol). The mixture was heated at 85° C. for 12 h and then concentrated and purified via column chromatography on silica gel (0 to 50% EtOAc in hexanes) delivered 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.360 g). 1H NMR (400 MHz, CD3OD) δ=8.58 (s, 2H), 7.87 (d, J=5.1 Hz, 1H), 7.66-7.63 (m, 1H), 7.28-7.23 (m, 1H), 5.14 (br. s., 1H), 4.76 (d, J=13.9 Hz, 1H), 3.83 (d, J=11.3 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.40 (s, 1H), 2.69-2.58 (m, 1H), 2.47 (dt, J=3.6, 12.0 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 491.0 (M+H)+. GK-GKRP IC50 (Binding)=0.362 μM; GK-GKRP EC50 (LC MS/MS-2)=0.470 μM.
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O-:22])=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CCC1CN2CCC1CC2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([O-])c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 1.22g dihydroquinidine (0.0037 mol) in 30mL of CH2Cl2 was added 0.78mL of Et3N (0.0056 mol; 1.5 eq), followed by 0.71mL of p-chlorobenzoyl chloride (0.005 mol; 2 eq) in 1mL CH2Cl2After stirring 30 minutes at 0° C. and 1 hour at room temperature, the reaction was quenched by the addition of 10% Na2CO3 (20mL). After separation, the aqueous layer was extracted with three 10mL portions of CH2Cl2. The combined organic layers were dried over Na2S04 and the solvent removed under vacuum. The crude product was purified as described above. Dihydroquinidine p-chlorobenzoate (1) was obtained in 91% yield (1.5g) as a white foam.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
To a magnetically-stirred solution of isovanillin (557 mmol, 85.0 g) in dry DMF (500 mL) at room temperature was added powdered K2CO3 (558 mmol, 77.1 g) in one portion followed by the dropwise addition of neat cyclopentyl bromide (614 mmol, 91.5 g; 65.9 mL). The resulting suspension was warmed to 60° C. and the reaction monitored by TLC until complete. Upon completion, the reaction mixture was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between H2O and EtOAc, the aqueous phase extracted with EtOAc and the combined organic layers were washed with H2O. The organics were dried (Na2SO4) and concentrated in vacuo to afford the alkylated product (317 mmol, 70.1 g; 57%) as a viscous oil which was of sufficient purity to be used as such in subsequent transformation.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:15]([CH:18](C(OCC)=O)[C:19]([O:21][CH2:22]C)=[O:20])([O-])=[O:16].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:7]1([C:6]2[O:16][N:15]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:5]=2[CH2:4][CH2:3][C:2]([F:13])([F:14])[F:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)CCC#Cc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Yield: 22.1 %

Procedure:
A solution of (5,5,5-trifluoropent-1-ynyl)benzene (215 mg, 1.09 mmol), diethyl nitromalonate (0.758 mL, 4.34 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.023 mL, 0.108 mmol) in toluene (3 mL) was heated to 170° C. for 150 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (9/1) provided methyl 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylate (72 mg). The compound had an HPLC ret. time=3.61 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14]O>ClCCl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14][Cl:3]
Reactant: OCc1cc(F)c(F)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(Br)c(CCl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
146 μl of thionyl chloride in 2.5 ml of dichloromethane are added dropwise to 300 mg of (2-bromo-4,5-difluorophenyl)methanol in 2.5 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7]/[C:8]/2=[CH:13]\[C:14](=[N:23]/[CH2:24][C:25](OCC)=[O:26])\[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.Cl.C(OC(=O)CN)C>CCO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH2:24][N:23]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH:13]=[C:8]12
Reactant: CCOC(=O)C/N=C(\C=C1/NCCc2c(OC)cccc21)c1cccc(OC)c1
Agent: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(C2=NCC(=O)N3CCc4c(OC)cccc4C3=C2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
ethyl 2-((E)-((Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethylidene)amino)acetate. 1-2. A mixture of 1-1 (5.8 g, 18.81 mmol) and glycine ethyl ester hydrochloride (13.1 g, 94 mmol) in EtOH (200 mL) was heated to 100° C. and stirred for 2 h. The reaction was then cooled to RT and the mixture was concentrated in vacuo. The residue obtained was taken up in DCM and washed with a 1M aq. solution of NaOH. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.0 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 395.3 (M+H+); UPLC rt 0.80 min.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCCC1.[OH-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-c3ccccc3)nc2c1
Yield: 26.5 %

Procedure:
To a mixture of 0.78 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of phenylboronic acid, 5 ml of tetrahydrofuran and 0.14 g of dichlorobis(triphenylphosphine)palladium (II), 3 ml of 10% aqueous solution of sodium hydroxide was added and heated to reflux for three hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3-phenyl pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 32”).