Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:15]([CH2:29][CH3:30])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][NH:21][CH2:20]1)[CH3:14].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:29]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:20]1)[CH3:30]
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: CCN(CC)CCOC1CNCCC1(OC)OC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 7.5 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 10.5 parts of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine, 7 parts of N,N-diethylethanamine, 1 part of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 17 hours at 60° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The whole was evaporated and the residue was taken up in acetonitrile. The solution was evaporated, yielding 14 parts (75%) of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl-]-4,4-dimethoxy-3-piperidinyl]oxy]ethanamine as a residue (intermediate 115).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22](OC)O)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[C:27](=[O:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28].C([SiH](CC)CC)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH2:22][NH:28][C:27](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:6][CH:7]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (Example 5a, 36 mg, 0.1 mmol), tert-butyl carbamate (35 mg, 0.3 mmol), triethylsilane (0.1 mL), and acetonitrile (0.5 mL) was added trifluoroacetic acid (0.03 mL). The mixture was stirred at RT for 40 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave tert-butyl 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)ethylcarbamate as a trifluoroacetic acid salt (23 mg, 0.043 mmol, 43% yield). MS found: (M+H)+=426.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][N:28]1[CH:32]=[N:31][N:30]=[CH:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][N:28]2[CH:32]=[N:31][N:30]=[CH:29]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nn1cnnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nn1cnnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-amino-1,2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4H-1,2,4-triazol-4-yl)terephthalamide. MS (Q1) 453 (M)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/B2OC(C)(C)C(C)(C)O2)[CH:11]=[CH:12][CH:13]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]2[N:38]([CH3:48])[C:39]([C:41]3[CH:46]=[CH:45][N:44]=[C:43](I)[N:42]=3)=[CH:40][C:34]=2[C:33]1=[O:49])=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]2[N:38]([CH3:48])[C:39]([C:41]3[CH:46]=[CH:45][N:44]=[C:43](/[CH:15]=[CH:14]/[C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=4)[N:42]=3)=[CH:40][C:34]=2[C:33]1=[O:49])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1c(-c2ccnc(I)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(/C=C/c2cccc(Cl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cn1c(-c2ccnc(/C=C/c3cccc(Cl)c3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 50 %

Procedure:
Cesium carbonate (0.143 g, 0.438 mmol), palladium tetrakis (0.051 g, 0.042 mmol) and 2-[(E)-2-(3-Chloro-phenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.116 g, 0.440 mmol) were added to a solution of 2-(2-Iodo-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (synthesised as reported in Example 9) (0.100 g, 0.22 mmol) in dioxane (5.0 ml) under argon atmosphere. Argon was bubbled for 5 minutes, the vial was closed and the reaction mixture was heated by microwave irradiation for 30 minute at 100° C. for two cycles. In order to affect completion, a refresh of the catalyst and the base and two more cycles at the microwaves were carried on. The solvent was removed under vacuum, the residue was taken into DCM (5.0 ml), which was washed with a saturated solution of NaHCO3 (1×5.0 ml), brine (1×5.0 ml), and it was dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography, over silica gel, using DCM/MeOH (9.9:0.1) as eluent, to afford 2-{2-[(E)-2-(3-Chloro-phenyl)-vinyl]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester yellow solid (0.051 g, 0.110 mmol, 50%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:11]=2[Cl:25])[CH:5]=[N:4]1)[CH3:2].[CH2:27]=O>ClCCl.C(OCC)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([N:20]3[CH2:21][CH2:22][CH2:23][O:24][CH2:27]3)[C:11]=2[Cl:25])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(NCCCO)c2Cl)c1O
Reactant: C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCCOC3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 350 mg (0.87 mmol) of 1-ethyl-4-(2-chloro-3-(3-hydroxypropylamino)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 1 mL of dichloromethane was diluted with 10 mL of diethyl ether and treated with 0.10 mL (1.3 mmol) of formalin. After stirring for 40 hours at ambient temperature, the reaction mixture contained a white precipitate and approximately one third of the starting material remained according to HPLC analysis. The solution was decanted and the solids remaining were dissolved in dichloromethane. The resulting solution was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 160 mg (43 percent of theory) of the title compound as tan crystals.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]([CH3:16])[C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1Nc2ncc(Br)cc2CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)OCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.3, 0.707 mmol) in DMF (1.4 ml) was added 55% sodium hydride in oil (0.778 mmol). The RM was stirred for 5 min at rt then was added iodomethane (0.778 mmol) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc, washed with saturated NaHCO3, with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.64 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>ClCCl.OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11]
Reactant: O=[N+]([O-])O
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#CCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a solution of 2,6-dichloro-phenyl-acetonitrile (15.0 g, 80.62 mmol) in the dichloromethane (50 mL) and H2SO4 (40 mL) is added (slowly) a mixture of H2SO4 (14 mL) and HNO3 (5.5 mL) at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, warned to room temperature for half hour, and then concentrated to remove organic solvent. The solution is poured into a beaker containing ice-water (400 mL) to give a crystalline precipitate, which is collected by vacuum filtration and washed with water to afford the product (20.44 g, 82.4%).
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)N>CC(O)=O.CCO>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:12][NH:2]/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:19]=1)#[N:21]
Reactant: CCOC(=O)/C(C)=C/N(C)C
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C(C)=C/NNc1cc(C#N)ccn1
Temperature: 90 °C
Yield: 62.1 %

Procedure:
A solution of ethyl(E)-3-(dimethylamino)-2-methylprop-2-enoate (668 mg, 4.25 mmol) and 2-hydrazinylpyridine-4-carbonitrile (570 mg, 4.25 mmol, PREPARATION 2) in 2 mL HOAc and 10 mL EtOH was charged to a flask and the mixture was heated to 90° C. for 30 min. Cooled to room temperature and removed the solvent. The residue was dissolved in ethylacetate and water, aqueous basified with NaHCO3 sat (pH=8), extracted with ethylacetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate and then purified by silica gel chromatograph to give 0.65 g of the title compound (62%). [M+H] Calc'd for C12H14N4O2, 247; Found, 247.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:6])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.O[CH:31]([C:34]1[CH:50]=[C:49]2[N:37]([CH2:38][C:39]3[C:40]2=[N:41][C:42]2[C:47]([CH:48]=3)=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36](=[O:51])[C:35]=1[CH3:52])[CH2:32][CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:52][C:35]1[C:36](=[O:51])[N:37]2[C:49](=[CH:50][C:34]=1[CH:31]([O:4][C:3](=[O:5])[C:2]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:1])[CH3:6])[CH2:32][CH3:33])[C:40]1=[N:41][C:42]3[C:47]([CH:48]=[C:39]1[CH2:38]2)=[CH:46][CH:45]=[CH:44][CH:43]=3
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)C(C)(C)NC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture containing 2-methyl-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propionic acid (406 mg, 2.0 mmol) and dicyclohexylcarbodiimide (432 mg, 2.0 mmol) in CH2Cl2 (3 mL) under an argon atmosphere were added (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (153 mg, 0.5 mmol) and 4-dimethylaminopyridine (25 mg). The resulting mixture was allowed to stir at room temperature for 4 d and then was poured into CH2Cl2, washed successively with 5% aqueous NaHCO3, 0.5N HCl and H2O, and dried over sodium sulfate. Removal of the solvent in vacuo and purification of the residue by column chromatography (silica gel) eluting with a solvent gradient of 1.5-5% MeOH/CH2Cl2 afforded the title compound as an off-white solid. 1H NMR (CDCl3) d 8.33 (s, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.33 (s, 1H), 5.92 (dd, J=7.5, 6.3 Hz, 1H), 5.25 (s, 2H), 5.10 (br s, 1H), 2.38 (s, 3H), 2.08-1.82 (m, 2H), 1.56 (s, 3H), 1.55 (s, 3H), 1.41 (s, 9H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.C(NC(N)=[S:26])(=O)C.C(OCC)(=O)C>C(O)C>[SH:26][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CCBr)cc2)cs1
Reactant: CC(=O)NC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CCS)cc2)cs1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a suspension of N-(4-{2-[4-(2-bromoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (353.3 mg, 1.000 mmol) in ethanol (4 ml) was added 1-acetyl-2-thiourea (177.4 mg, 1.501 mmol), and the mixture was heated under reflux for 7 hr. 1-Acetyl-2-thiourea (176.6 mg, 1.495 mmol) was added, and the mixture was heated under reflux for 17 hr. The mixture was cooled to room temperature, ethyl acetate (10 ml) was added, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and purified twice by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 21 g, ethyl acetate:hexane=2:3→1:1) to give N-(4-{2-[4-(2-sulfanylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (210.4 mg, 0.687 mmol, 68.7%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]2=[O:21])[CH2:3]1
Reactant: CC1CC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC1CC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 130 °C
Yield: 13.4 %

Procedure:
A mixture of 0.5 g of 3-methyl-1-indanone, 1.37 g oxindole and 5 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 130° C. overnight to yield a reddish-brown suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 120 mg of 3-(3-methylindan-1-ylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:5]3[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]=3)[CH2:20][CH2:19]2)=[O:23])=[CH:27][CH:26]=1
Reactant: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3)CC2)n1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
A mixture of 1-[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (80.0 mg, 0.255 mmol), 4-chlorobenzylamine (32.0 mg, 0.255 mmol), EDCI (49.0 mg, 0.255 mmol), HOBt (35.0 mg, 0.255 mmol) and N-methylmorpholine (26.0 mg, 0.255 mmol) in CH2Cl2 (5 mL) was stirred for 20 h (reaction progress monitored by LCMS). The solvent was removed under vacuum, and the residue was purified by preparative HPLC to yield 75 mg of the title compound as a white solid. MS (ES+): m/e 437.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:15][CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:15](\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccccc1F
Yield: 126 %

Procedure:
2-Fluorobenzaldehyde (5.0 g, 40.3 mmol) was dissolved in 150 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (42 g; 116 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo, then dissolved in ether and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (10.57 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.26-7.38 (m, 3H), 7.17 (m, 2H), 4.28 (q, J=7.12 Hz, 2H), 2.04 (s, 3H), 1.35 (t, J=7.12 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH-:6].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[C:18]=[S:19]
Reactant: [NH-]Cc1ccccc1C(F)(F)F
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN=C=S
Reaction time: 0.5 h

Procedure:
A solution containing 2-trifluoromethylbenzylamide (3.50 g, 0.02 mol) in 50 ml of dichloromethane and a solution containing sodium bicarbonate (3.4 g, 0.04 mol) in 55 ml of water are added simultaneously over one hour at a temperature close to 20° C. to a solution of thiophosgene (2.28 g, 0.02 mol) in 15 ml of dichloromethane. Agitation is carried out for 30 minutes. The reaction mixture is decanted and the organic phase washed with 100 ml of water then with 100 ml of a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The expected compound is obtained in the form of an oil (3.50 g, 81%). Considering its reactivity, it is used immediately for the following reaction.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CC(O)=O>[CH2:2]([O:3][C:4]([C@H:6]1[CH2:12][CH2:11][C@H:9]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.0 g, 29.0 mmol) and tert-butyl carbazate (3.9 g, 29.4 mmol) in dichlorometane (250 mL) and AcOH (4 mL) was added NaBH(OAc)3 (18.7 g, 88.0 mmol) gradually at 0° C. After addition, the mixture was stirred at the same temperature for 3 h, then allowed to warm to room temperature and stirred for 20 h. The reaction mixture was poured into saturated aqueous Na2CO3 solution and extracted with DCM. The DCM extracts were washed with brine×2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound D1-1 (3.0 g, 36%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:27])([F:28])[F:26])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=4[F:24])[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.105) (0.465 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.43 g), which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([CH3:12])=[CH:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:9]([CH3:12])[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CC(=CO)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 36.9 %

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-methylpropenol (5.5 g, 21 mmol) and pyridinium chlorochromate (5.5 g) in 150 mL dichloromethane was stirred for 16 hours. The mixture was concentrated in vacuo and the dark residue extracted with several 50 mL volumes of hexane. The hexane solution was chromatographed on silica gel eluting with 2% ethyl acetate in hexane to give 2.0 g of the title compound; m.p. =77°-80° C.
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=O)[C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:11][C:4]1[C:5]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])=[CH:6][NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1c(C(=O)O)c[nH]c1C=O
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O

Procedure:
5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid (500 mg, 3.27 mmol) reacted with 1-methylpiperazine (0.43 mL, 3.92 mmol) to give 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([C:11]([F:14])([F:13])[F:12])=[N:5]1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][C:8]1[N:4]([CH2:3][CH2:2][O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[N:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7]=1[OH:10]
Reactant: Cc1c(O)c(C(F)(F)F)nn1CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(O)c(C(F)(F)F)nn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ol (600 mg, 2.86 mmol; Kenkyu Hokoku—Asahi Garasu Kogyo Gijutsu Shoreikai, 1988, 51, 139–49) in dichloromethane (10 ml) and ethyl acetate (4 ml) was added para-toluenesulphonic acid (27 mg, 0.14 mmol) followed by 3,4-dihydro-2H-pyran (340 μl, 3.7 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (60:40, by volume) to provide the title compound (560 mg) as white solid.