Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:2].[C:16]([C:19]1[C:20](=[O:30])[O:21][C:22]([OH:29])=[C:23]([C:26](=O)[CH3:27])[C:24]=1[OH:25])(=[O:18])[CH3:17]>[Pd].C(O)C>[C:16]([C:19]1[C:20](=[O:30])[O:21][C:22](=[O:29])[C:23](=[C:26]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5](=[O:6])[NH:4][O:3][CH2:1][CH3:2])[CH:8]=2)[CH3:27])[C:24]=1[OH:25])(=[O:18])[CH3:17]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCONC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCONC(=O)c1cccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1
Reaction time: 1 h

Procedure:
A solution of 2.0 g. (0.0095 mol) of 3-ethoxycarbamoylnitrobenzene in 100 ml. of 2B ethanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 1 hour, the catalyst was filtered and to the filtrate was added 1.71 g. (0.0095 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyranone. The mixture was heated under reflux for 1.5 hours, cooled, and the product filtered to yield 5-acetyl-4-hydroxy-3-[1-(3-ethoxycarbamoylphenylamino)ethylidene]-2H-pyran-2,6-(3H)-dione, m.p. 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1
Reactant: C[C@H]1Nc2nc(Cl)ncc2NC1=O
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
To a stirred solution of (7R)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one (4.2 g, 21.15 mmol) in dichloromethane (350 mL) was added triethylamine (29.61 ml, 211.5 mmol), cupric acetate (7.69 g, 42.30 mmol) and 3-cyanophenyl boronic acid (6.62 g, 42.30 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 24 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (Yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.66 (d, J=6.9 Hz, 3H), 4.55 (q, J=5.1 Hz, 1H), 5.98 (br s 1H), 7.16 (s, 1H), 7.50-7.53 (m, 1H), 7.59-7.68 (m, 1H), 7.72 (t, J=7.8 Hz, 1H) and 7.81-7.83 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9](Cl)[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9]([NH:26][CH:23]([CH3:25])[CH3:24])[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Reactant: CC(C)N
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Temperature: 25 °C

Procedure:
A solution of 215 mg of 2-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester and 388 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated to provide 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester as a light yellow solid. MS (M+H+)=350.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:25])([CH3:24])[C:17]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:31]=[C:32]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:26]=2)=[CH:10][CH:11]=[C:12]1[C:32]#[N:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from tert-butyl-2-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.03 (s, 1H), 7.35 (d, J=1.79 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 7.23 (dd, J=1.79, 8.31 Hz, 1H), 7.12 (d, J=8.36 Hz, 1H), 6.44 (d, J=3.81 Hz, 1H), 4.25 (s, 2H), 1.55 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:4]=2[S:5][CH:6]=1.[N+:14]([O-])([OH:16])=[O:15]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:4]=2[S:5][CH:6]=1
Reactant: COc1cc2c(Cl)csc2cc1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(Cl)csc2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophene (0.39 g) was dissolved in ethyl acetate (26 ml). To the solution was gradually added a solution of nitric acid in dichloromethane (2M, 0.9 ml) at room temperature. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water and extracted with ethyl acetate and evaporated to dryness. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: Cc1ccc(C#N)cc1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C#N)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-cyanoanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-cyanoanilino)acetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:14][C:13]([CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:12][N:11]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][C:13]2[O:14][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:11][N:12]=2)[CH2:21][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{5-[(2,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}-N-piperidin-4-ylpropanamide (200 mg) in N-methylpyrrolidinone (4 ml) was added benzaldehyde (115 μl) and glacial acetic acid (0.04 ml). The reaction mixture was then heated at 80° C. for 1 hour before being left to cool and sodium triacetoxyborohydride (242 mg) added. The mixture was then stirred at room temperature for 8 hours before being evaporated to dryness and the residue separated into basic and non-basic components using SCX chromatography. Basic fractions were combined and evaporated to dryness. The residue was purified by RPHPLC (MeCN with NH3 buffer). Fractions containing the desired product were combined and evaporated to dryness to give the title compound. (92 mg).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](C(F)(F)F)=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:38][C:39](=O)[C:40]([F:43])([F:42])[F:41]>>[F:34][C:33]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([C:33]([F:36])([F:35])[F:34])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:38]=[C:39]([C:40]([F:43])([F:42])[F:41])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Reactant: O=C(CBr)C(F)(F)F
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(C(F)(F)F)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-bromo-1,1,1-trifluoroacetone.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O[N:21]1C2C=CC=CC=2N=N1.O.N>ClCCl>[C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([NH2:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C1=CN(c2ccccc2)N(C(=O)O)N1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C1=CN(c2ccccc2)N(C(N)=O)N1
Temperature: -78 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
In a nitrogen atmosphere, 630 mg of 3-phenyl-5-trimethylsilanyl-1H-[1,2,3]triazole-2-carboxylic acid which is the compound prepared in the above 2) was dissolved in 5 ml of dichloromethane, 671 mg of 1-hydroxybenzotriazole monohydrate and 907 mg of a water-soluble dichlorohexyl carbodiimide were added thereto, the reaction solution was cooled down to −78° C. and ammonia gas was introduced thereinto followed by stirring for 2 days. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was separated and purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to give 550 mg of the title compound as a white solid.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.ClCCl>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: CC(C(N)=O)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)C(N)=O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a suspension of 2-(piperazin-1-yl)propanamide dihydrochloride (0.305 g, 1.33 mmol) in DMSO (1.5 mL), was added 1,1,3,3,-tetramethylguanidine (0.398 g, 3.45 mmol) at rt. The reaction mixture was stirred for 15 min. After that time 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.20 g, 0.664 mmol) was added as a solid in a single portion. The resulting mixture was stirred at 90° C. for 3.5 h. After that time the reaction was cooled to rt and diluted with dichloromethane (50 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 93:7 dichloromethane/methanol) to give 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide (0.080 g, 28%) as a light yellow solid: mp 149-150° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (br s, 1H), 7.65-7.79 (m, 2H), 7.30 (s, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.78 (s, 1H), 6.58 (s, 1H), 4.48 (br s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.64 (br s, 4H), 3.55 (br s, 2H), 2.54 (br s, 4H), 2.45 (t, 2H); ESI MS m/z 439 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K+].[Br-]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:24]2)=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: c1ccc(CCCCN2CCNCC2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Cl)cc1)N1CCN(CCCCc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 86%. White crystals, m.p. 230–232° C.; 1H NMR (DMSO-d6): δ 11.43 (br,1H), 7.51–7.43 (d-like m, 2H), 7.33–7.15 (m, 7H), 4.33–3.95 (br, max at 4.21 and 4.10 ppm; 2H), 3.72–3.36 (br m, 4H), 3.22–2.96 (br, max at 3.10 ppm, 4H), 2.62 (t, J=7.54 Hz, 2H), 1.84–1.69 (m, 2H), 1.69–1.54 (m, 2H) ppm; IR (KBr): ν 1736, 1720 (C═O) cm−1.
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c12
Yield: 53 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 40 mg (53%) of product 13 as a white solid, mp 190-192° C. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=6 Hz, 6H), 2.60 (s, 3H), 5.05-5.14 (m, 1H), 6.88 (d, J=8 Hz, 1H), 6.98 (d, J=9 Hz, 2H), 7.23 (t, J=8 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 12.45 (s, 1H). LC-MS (CI): m/z 360.1 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S.0.07CH2Cl2: C, 62.61; H, 5.00; N, 3.83; S, 8.77; Cl, 11.05. Found: C, 62.32; H, 5.01; N, 3.77; S, 9.08; Cl, 10.93.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.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>[F:14][C:11]([F:12])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (8.36 g, 18 mmol), trimethylsilylacetylene (5.1 mL, 37 mmol), Et3N (7.66 mL, 55 mmol), PdCl2(PPh3)2 (64 mg, 0.5 mol %) and PPh3 (48 mg, 1 mol %) in THF (40 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (10 mg, 0.3 mol %) was added.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([N:7]([CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.1 %

Procedure:
To a solution of tert-butyl 4-((4-fluorobenzylamino)methyl)benzylcarbamate (654 mg, 1.90 mmol, Aldrich) in CH2Cl2 (5 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (497 mg, 0.50 mmol, Aldrich) and diisopropylethylamine (1.34 mL, 9.50 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution and brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (604 mg, 53%) as a white solid. MS (ESI): m/z 566.9.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH3:19][C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)=[N:10][CH:9]=1
Reactant: CCOC(=O)c1nc(C)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(Nc2cncnc2)c(C(=O)O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
6-Methyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid ethyl ester (300 mg, 1.15 mmol) was dissolved in a THF/ethanol (5 ml/1 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (4.7 ml, 1N aqueous solution). The reaction mixture was allowed to warms to ambient temperature and stirred at that temperature for 1 hour. The pH value was subsequently adjusted to acidic and the resulting suspension was filtrated. The precipitate was washed with water and ethyl acetate and dried to yield the product as light yellow solid (185 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].C(N(CC)CC)C.[CH3:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](Cl)=[O:45]>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:44](=[O:45])[CH2:43][C:42]([CH3:48])([CH3:47])[CH3:41]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 9.9 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazin-1-yl)methanone (100 mg, 0.209 mmol) was stirred in dichloromethane (1 mL) with triethylamine (53 mg, 0.073 mL, 0.521 mmol) at 0° C. 3,3-Dimethylbutanoyl chloride (42 mg, 0.313 mmol) was added and the reaction allowed to stir for 2 hours. The reaction mixture was washed with water and the organic phase was purified by reverse phase acidic preparative HPLC to afford the title compound (12 mg). MS (ESI) m/z 578.5 [M+H]+
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([NH2:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:12]([NH:14][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCNC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (2 g, 12.8 mmol), and ethylamine (6.4 mL, 12.8 mmol), and sodium triacetoxyborohydride (8 g, 38 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([NH:14][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NC2CCCCC2)CS1

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (1.00 g) in ethanol (30 mL) was added cyclohexylamine (0.88 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained powder was washed with ethyl acetate to give the title compound (599 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[N:29]=[CH:30][CH:31]=[C:32]2[C:33]=1[CH:34]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:18]3)=[CH:14][CH:15]=1)=[N:36]2
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 33-2 (0.64 g, 2.5 mmol), 3-1 (0.88 g, 2.5 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (14 mL) was heated to 120° C. for 4.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→70% ethyl acetate/hexane) gave the title compound as a foam. MS (M+H+): calculated=471.98, observed=472.1.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CCOCC>COCCOCCOC>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1cccc(Cl)c1

Procedure:
Ethyl 2,4-difluorobenzoate (6.0 g), K3PO4 (7.5 g) and 3-chlorophenol (4.1 g) were stirred at 110° C. in diglyme (25 mL) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.