Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:16])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1ncc(-c2ccccc2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1ncc(-c2ccccc2)nc1C(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 3-amino-6-phenylpyrazine carboxylic acid (0.10 g, 0.47 mmol) in dichloromethane (3 mL) were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.11 g, 0.56 mmol), 1-hydroxybenzotriazole (HOBT, 75 mg, 0.56 mmol), and N-methylmorpholine (NMM, 56 mg, 0.56 mmol) at room temperature. The reaction was stirred for 15 min before benzylamine (0.56 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL) and aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford product (91 mg, 67% yield) as light yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.38 (br s, 1H), 7.84 (dd, 2H), 7.45 (m, 2H), 7.38 (m, 6H), 4.70 (d, 2H); MS (EI) for C18H16N4O: 305 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[C:11]([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])[CH3:12].[H-].[Na+]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cc(F)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Temperature: 25 °C
Yield: 82.3 %

Procedure:
1.35 g 4-Fluoro-2-methyl-benzonitrile, dissolved in DMF, was added to 2.11 g 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 0.6 g sodium hydride in 30 mL DMF. The mixture was stirred at room temperature (rt) until the reaction was complete. The reaction was quenched with water. The aqueous layer was extracted with ethylacetate (AcOEt) or methyl tert. butyl ether (MTB ether). The combined organic layers were washed with brine, dried and concentrated to give 2.6 g (yield 81%) 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. Mass: (C18H24N2O3): calcd. 316. found 261 [M+H−t(C4H9)]+
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH:28]1([NH:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:40]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ccc(NC2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(NC2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-cyclohexyl-p-phenylenediamine Rf value: 0.8 (silica gel, methylene chloride/methanol=10:1) C29H28N2O3
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:26]#[N:27])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]2[C:20](=[C:26]([NH2:27])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1
Reactant: Cc1ccc(Br)c(C#N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-methylpicolinonitrile (from step 2) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-70% ethyl acetate in hexane to give 3-methylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (methanol d-4): δ 8.85 (d, 1H), 8.38 (d, 1H), 7.72 (d, 1H), 7.53-7.61 (m, 2H), 7.34-7.38 (dd, 1H), 2.76 (s, 3H). LRMS [M+H]=210.1
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]2[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=2)=[O:7])=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2N)ccc1OC
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Temperature: 40 °C
Reaction time: 42 h
Yield: 102.6 %

Procedure:
555 mg of 2,6-dimethoxynicotinic acid and 581 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placed in a flask under nitrogen. 778 mg of acetic acid (1 RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound B1) and 2 mg of 4-dimethylaminopyridine both as solution in dichloromethane are added and the solution stirred for 1 h at 40° C., than 42 h at room temperature. The reaction is quenched with 5 ml of water. After phase separation the organic layer is washed with 2.5 ml of saturated potassium hydrogencarbonate solution. After drying the organic layer with magnesium sulfate the solvent is removed to give 1.227 g of the crude title compound which are used for the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OCC(F)(F)F)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)COc1ccc(CBr)nc1
Temperature: 80 °C
Yield: 13 %

Procedure:
Add 2-methyl-5-(2,2,2-trifluoroethoxy)-pyridine (2.5 g, 13.1 mmol), NBS (2.3 g, 13.1 mmol) and benzoyl peroxide (50 mg) to a flask containing carbon tetrachloride (30 mL). Heat the mixture at 80° C. in a sealed flask for 16 h. Cool the flask, add NBS (1.1 g, 6.5 mmol) and benzoyl peroxide (100 mg), then continue heating at 80° C. for an additional 5 h. Cool the mixture, dilute with DCM, then wash with saturated sodium bisulfite (10 mL). Collect the organic layer and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate (460 mg, 13%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:26].C(=O)(O)[O-].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([F:26])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](F)[C@@H]1O
Temperature: 0 °C
Reaction time: 9 h

Procedure:
To a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (100 mg) in anhydrous diethyl ether (6 ml) cooled in an ice-bath was added 70% hydrogen fluoride-pyridine (0.24 ml). The mixture was stirred at 0° C. for 9 hours, ice was added and the reaction mixture was neutralized by addition of solid sodium bicarbonate (1.2 g) at 0° C. and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated to afford the crude title compound as an oil (65 mg). This crude material was purified by chromatography on silica gel (10 g, elution with ethyl acetate:cyclohexane, 2:8) and the resulting material (35 mg) was crystallized from a diethyl ether/pentane mixture to afford the title compound as a white solid, m.p. 98°-99° C.
Reaction SMILES: Cl[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]3[CH:10]=[N:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]2[N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:19][CH:20]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(Cl)n1-c1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=c1c2cnn(-c3ccccc3)c2nc(N2CCN(c3ccccc3)CC2)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one from step C (20.0 mg, 0.056 mmol) in DCM (1.0 mL) are added 1-phenylpiperazine (17.1 μL, 0.112 mmol) and TEA (15.6 μL, 0.112 mmol). The mixture is stirred at room temperature overnight. After removal of the solvent, the residue is purified by preparative LCMS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 8.11 (d, 2H), 7.52 (m, 4H), 7.38-7.29 (m, 5H), 7.00 (m, 3H), 3.44 (t, 4H), 3.07 (t, 4H); HPLC-MS calculated for C27H23ClN6O (M+H+) 483.2. Found: 483.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC#N
Product: N#CC(=C(Nc1cc(Cl)cc(Cl)c1)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 49 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsulfanyl-2-propenenitrile (0.90 g, 2.1 mmol), cyclobutylamine (0.50 ml, 6.3 mmol) and acetonitrile (2 ml) were stirred for 40 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) gave 0.47 g (49%) of the title compound. 179.5-181.5° C. (EtOAc) 1H NMR (200 MHz, CDCl3): δ=1.65 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 3.65 (sextet, 1H), 6.88 (d, 2H), 7.18 (t, 1H), 7.47 (d, 2H), 7.78 (d, 2H); EI SP/MS: 459 (M+4), 357 (M+2) 455 (M+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([C:15]2[O:16][C:17](=O)[CH2:18][N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:15]([NH:19][CH2:18][C:17]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)(=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C1CN=C(c2ccccc2)O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCc1nc2ccccc2s1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
2-Aminothiophenol (1.2 ml) is added to a solution of 2-phenyl-4,5-dihydro-1,3-oxazol-5-one (1.8 g) in acetic acid (14 ml), and the mixture is stirred for one hour while heating it at 40° C. Water is added to the reaction mixture, and the resulting precipitate is filtered off to give 2-(benzoylaminomethyl)benzothiazole (0.75 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:10](=[O:27])[CH2:11][NH:12][C@H:13]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]([OH:27])[CH2:11][NH:12][C@H:13]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CN[C@@H](CC(C)C)C(=O)OCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
To a solution of 5.0 g (10.9 mmol) of N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-oxo-5-methylhexyl]-L-leucine, 2-(trimethylsilyl)ethyl ester in a mixture of 150 ml of tetrahydrofuran and 50 ml of water cooled in an ice-water bath was added 2.1 g (54.5 mmol) of sodium borohydride. After 5 minutes, the reaction was poured into 300 ml of water and extracted with 600 ml of ethyl acetate. The organic extract was rinsed further with water and brine, dried (magnesium sulfate) and concentrated in vacuo to yield 4.7 g of crude product. Flash chromatography on 140 g of LPS-1 silica gel eluted with 10:1, petroleum ether:acetone yielded 3.5 g of the title compound as an oil. By 13C-NMR analysis, material prepared in this manner is essentially a 1:1 mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:21][CH:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1>>[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:2]3[N:3]=[C:4]([N:18]4[CH2:19][CH:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Product: COc1cc(Nc2nc3c(c(N4CC(N(C)C(=O)OC(C)(C)C)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 49.4 %

Procedure:
tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate (Preparation Hn) (147 mg, 0.340 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (76 mg, 0.340 mmol) were combined as per Example 26 to give the crude tert-butyl 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate (104 mg, 0.168 mmol, 49.4% yield) which was used without further purification. LC-MS (M+H)+=620.4.
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1)[CH3:6])(=[NH:4])=[O:3].[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[S:18]>C(#N)C>[CH3:1][S:2](=[O:3])([CH:5]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=1)[CH3:6])=[N:4][C:17]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[S:18]
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=N)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(=S)n1ccnc1
Temperature: 60 °C

Procedure:
To a solution of 5-[1-(methylsulfonimidoyl)ethyl]-2-(trifluoromethyl)pyridine (E) (400 mg, 1.59 mmol) in acetonitrile (5 mL), 1,1′-thiocarbonyldiimidazole (353 mg, 1.59 mmol, 1 eq) was added and stirred over night. A second aliquot of 1,1′-thiocarbonyldiimidazole (71 mg, 0.317 mmol, 0.2 eq) was added and the mixture heated to 60° C. for two hours. The solvent was removed under reduced pressure, the residue dissolved in CHCl3 and washed five times with water. The organic phase was dried (Na2SO4) and chloroform was removed under reduced pressure. N-(Methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)-1H-imidazole-1-carbothioamide (Y) was obtained as an orange-brown residue, which was dried in the high vacuum over night (371 mg, 1.02 mmol, 64%). A 1:1 mixture of diastereomes with a purity of 94% was observed by UPLC-UV/ELSD and NMR, which was sufficient for subsequent conversions. Higher purities were obtained by filtration of the residue through a plug of silica (7.5% MeOH in CHCl3). 1H NMR (CDCl3, 400 MHz): δ=1.83 (d, J=7.1 Hz, 1.5H, CHCH3, diastereomer 1); 1.86 (d, J=7.1 Hz, 1.5H, CHCH3, diastereomer 2); 2.86 (s, 1.5H, S—CH3, diastereomer 1); 2.89 (s, 1.5H, S—CH3, diastereomer 2); 4.32 (q, J=7.1 Hz, 0.5H, CHCH3, diastereomer 1); 4.37 (q, J=7.1 Hz, 0.5H, CHCH3, diastereomer 2); 7.68-7.85 (m, 2H, Ar), 7.97-8.14 (m, 2H, Ar), 8.67-8.82 (m, 2H, Ar), UPLC-MS (ESI+): mass calc'd for C13H12F3N4OS2 (M+H+): 363.0, found 363.1, UPLC-MS (ESI+) mass calc'd for C13H14F3N4OS2 (M−H+): 361.0, found 361.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:20]=[N:21][C:22]([O:29][CH3:30])=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:20]=[N:21][C:22]([O:29][CH3:30])=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C(F)(F)F
Product: COc1ncc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C(F)(F)F
Yield: 79 %

Procedure:
The title compound was synthesized as described for Example 1 in 79% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-1H-isoindol-3-amine (680 mg, 1.42 mmol), pyrimidin-5-ylboronic acid (211 mg, 1.70 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (s, 1 H) 9.05 (s, 2 H) 8.41 (d, 1 H) 7.91 (d, 1 H) 7.87 (d, 1 H) 7.66-7.72 (m, 2 H) 7.56 (td, 1 H) 7.44-7.52 (m, 2 H) 7.28 (dd, 1 H) 6.72 (br. s., 2 H) 3.94 (s, 3 H); MS (ES+) m/z 480 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>CN(C)C=O>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccc2[nH]1
Yield: 20.03 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1H-benzo[d]imidazole-2-carboxylic acid (100 mg, 0.617 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (161 mg, 0.617 mmol) using N,N-dimethyl formamide as the solvent. The product was purified by flash chromatography and recrystallized from chloroform, respectively. Yield 20.03%. 1H-NMR (400 MHz; CDCl3): δ 1.33 (d, 3H), 4.32 (dd, 1H), 4.47 (dd, 1H), 4.64-4.75 (m, 1H), 6.59 (d, 1H), 7.34-7.41 (m, 2H), 7.50 (d, 1H), 7.52-7.56 (m, 1H), 7.62 (d, 1H), 7.81-7.87 (m, 2H), 8.00 (d, 1H), 8.42 (d, 1H), 10.87 (s, 1H).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 78 %

Procedure:
As described for Example 48b, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (90 mg, 78%) which was obtained as a light yellow solid. MS: m/e=516.4 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([OH:18])=O)[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.CN(C)C=O.S(Cl)(Cl)=O.[NH2:30][CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:18])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Reactant: CC(C)N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Reaction time: 65 h

Procedure:
To a solution at room temperature of 6.0 g (20.6 mmoles) of cis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid and ca. 1 ml of anhydrous DMF (dimethylformamide) in 300 ml of anhydrous CH2Cl2 was added dropwise a solution of 8.95 ml (123.6 mmoles) of thionyl chloride in 50 ml of anhydrous CH2Cl2. After addition, the solution was stirred and refluxed for 2.5 hours. The solvent and excess SOCl2 were then removed under reduced pressure and the residue was flashed down twice with anhydrous benzene to remove traces of SOCl2. The residue was redissolved in ca. 200 ml of CH2Cl2 and a solution of 7.7 g (130 mmoles) of 2-aminopropane in ca. 50 ml of CH2Cl2 was added. Heat was evolved. The solution was mixed well and allowed to stand in a stoppered flask at room temperature for 65 hours.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22].CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22]
Reactant: CC(O)CCCCCCCCCOc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)CCCCCCCCCOc1ccc2ccccc2n1

Procedure:
The above alcohol was oxidised under Swern conditions (dimethyl sulphoxide, 0.615 g; oxalyl chloride, 0.38 ml; triethylamine, 2.74 ml) to give after column chromatography 11-(2-quinolinyloxy)undecan-2-one (0.96 g).