Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][NH:3][CH2:2]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(c2ccccc2)CCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
The mixture of ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (520 mg, 2 mmol), cupric acetate (728 mg, 4 mmol), phenyl boronic acid (490 mg, 4 mol) and pyridine (0.35 mL, 4 mmol) in dry DCM (20 mL) was stirred at ambient temperature for 3 days. The mixture was filtered though a pad of celite. The filtrate was concentrated in vacuo and then purified by chromatography on silica gel eluting with EtOAc-Hexane (7:93) to give the title compound (53 mg); 1H-NMR (CDCl3): δ 8.66 (1H, s), 7.42 (1H, d), 7.26-7.18 (4h, m), 7.10-7.00 (2H, m), 7.69 (2H, m), 6.67 (1H, t), 5.22 (1H, m), 4.40-4.18 (3H, m), 4.04-4.01 (1H, m), 3.98-3.88 (1H, m), 3.58-3.52 (1H, m), 3.22-3.15 (1H, m), 3.08-3.02 (1H, m), 1.27 (3H, t); MS (ES): 335 (MH+).
Reaction SMILES: Br[C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].[N-:32]=[N+:33]=[N-:34].[Na+]>C(#N)C>[N:32]([C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4])=[N+:33]=[N-:34]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)N=[N+]=[N-])c2c1
Yield: 108 %

Procedure:
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide (160 mg, 0.319 mmol) in actonitrile (15 mL) was added sodium azide (62 mg, 0.958 mmol). After being refluxed overnight, the resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 160 mg of the crude product.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=O)[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[S:43])[CH:5]=[CH:4][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 110.0 mg (0.25 mmol) ethyl 4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) and 121.0 mg (0.30 mmol) of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ 8.92 (1H, s), 8.06 (2H, t, J=8.5 Hz), 7.88-7.70 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.18 (4H, m), 6.03 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.38 (3H, s), 2.36 (2H, d, J=4.7 Hz), 1.56 (3H, t, J=7.1 Hz), 1.35 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[C:31]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:29]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][C:22]([CH3:41])([CH3:21])[C:31]=4[CH:30]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:12]1.Cl>O1CCOCC1>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)[CH:19]=2)[N:7]=[CH:6][N:5]=1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: CNc1cc(Cl)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(Nc2cccc(CN3CCN(C)CC3)c2)ncn1
Temperature: 150 °C

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (385 mg, 2.68 mmol, 1.1 equiv), 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.44 mmol) and 4N HCl in dioxane (7 mL) is heated in a sealed tube to 150° C. for 17.5 h. The solvent is removed and the residue diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM and DCM/MeOH (95:5). The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a beige solid: ESI-MS: 313.2 [MH]+; tR=1.00 min (purity: 100%, system 1); TLC: Rf=0.05 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Br:24]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Br:24]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Br
Reaction time: 1 h

Procedure:
16 g (0.049 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 160 ml of glacial acetic acid are treated slowly while stirring with 8.5 g of bromine in 10 ml of glacial acetic acid. After 60 minutes at room temperature, the reaction mixture is concentrated and the residue is partitioned between aqueous ammonia and methylene chloride. The aqueous phase is extracted several times more with methylene chloride. The combined organic extracts are dried and evaporated. The crude product is purified on 500 g of silica gel with methylene chloride/ethyl acetate (5:1) as the elution agent. From ethyl acetate/ether there is obtained 7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 188°-189°.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:12]([CH3:26])[C:11]3[C:10]([OH:27])=[CH:9][CH:8]=[C:7]([F:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([O:27][C:10]1[CH:9]=[CH:8][C:7]([F:28])=[C:6]2[C:11]=1[C:12]([CH3:26])=[C:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:5]2)[CH3:39]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 0 °C
Yield: 41.9 %

Procedure:
A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.064 g), (N-dimethylformamide (0.86 mL), potassium carbonate (0.071 g) and (R)-2-chloropropionic acid methyl ester (0.032 g) was stirred at 40° C. for 3 days. The mixture was cooled to 0° C., diluted with water (40 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume) gave title compound as a colourless oil (0.033 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Cl)cc1Sc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of 1.28 g. (0.01 mol) of p-fluorothiophenol and 2.82 g. (0.01 mol) of 2-iodo-4-chlorobenzoic acid in 20 ml. of pyridine is added 1.3 g. (0.01 mol) of potassium carbonate, with stirring. Additional pyridine is added until solution is clear and then 0.3 g. of cuprous chloride is introduced. The resulting mixture is refluxed overnight, poured into ice-water, stirred and filtered. The aqueous solution is acidified and filtered. The solid is dissolved in 5% sodium bicarbonate solution and this solution is extracted with ether. The aqueous solution is acidified, extracted with ether and the washed, dried extract is concentrated to give 4-chloro-2-(4-fluorophenylthio)-benzoic acid, m.p. 204°-213° C. The latter (6.5 g., 0.023 mol) is heated for one hour with 105 g. of sulfuric acid to obtain 2-fluoro-6-chloro-9-thioxanthone, m.p 222°-224° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:29]([CH3:30])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Dissolve 28.2 g (0.2 mol) p-fluoronitrobenzene into 300 ml tetrahydrofuran. Add a solution of which 56.4 g (0.2 mol) N, N-octadecylmethylamine and 20.3 g (0.2 mol) triethylamine are dissolved in 300 ml tetrahydrofuran into the above solution, while stirring. After the completion of the adding heat and reflux it for four days. 60.6 g (0.15 mol) N, N-octadecylmethyl-p-nitroaniline is obtained by recrystalization of the solution using ethyl alcohol and water after concentrating the above solution.
Reaction SMILES: [CH3:1][CH:2]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[Na+].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35]([NH:19][S:16]([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:1])(=[O:18])=[O:17])=[O:36])[CH3:23]
Reactant: CCCCCCCCCCCCCC(C)S(N)(=O)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)S(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A solution of 2-pentadecylsulfonamide (2.91 g, 10 mmoles) in DMF (40 mL dried over 3 Å sieves) was added dropwise to a stirred, 0° C. suspension of NaH (0.5 g, 21 mmoles of hexane washed) in 10 mL dry DMF. The mixture was stirred 30 minutes at 0° C., then warmed to room temperature for 3 hours. It was then cooled back to 0° C. and a solution of 2,6-diisopropylphenylisocyanate (2.14 mL, 10 mmoles) in 10 mL DMF was added dropwise. The mixture was allowed to warm to room temperature overnight, cooled to 0° C., and quenched by dropwise addition of 1N HCl (60 mL). The mixture was partitioned between EtOAc (300 mL) and H2O (100 mL). The organic layer was further washed with brine, dried, filtered, and evaporated to provide an oil which was flash chromatographed (silica gel, 4:1 hexane-EtOAc) to produce 3 g of an oil which solidified on standing (m.p. 65°-75° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[NH:18][S:19][C:15]=2[CH:14]=1)=[O:12].[Na]>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[N:18]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[S:19][C:15]=2[CH:14]=1)=[O:12]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)c1ccc2c(=O)[nH]sc2c1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(=O)n(C(=O)c3ccco3)sc2c1

Procedure:
A mixture of 2-furoyl chloride (0.1 mole) and 3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester, 1,1-dioxide, sodium salt, from example 3C, above, is refluxed in 100 ml of tetrahydrofuran for 3 hours. The reaction mixture is filtered hot and the filtrate is concentrated to give the product. The product is triturated with ether and air dried to give 2-(2-furoyl)-3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester, 1,1-dioxide.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Br[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)=[O:8]>>[OH:4][CH2:3][CH2:2][S:1][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=1)=[O:8]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: OCCS
Product: COc1cc(C(=O)CSCCO)cc(OC)c1OC
Yield: 76.9 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 2-mercaptoethanol (0.82 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 2.60 g) obtained in Reference Example 1 to give 2-(2-hydroxyethylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-12, 1.98 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([OH:25])[CH3:24])[CH3:20].[H-].[Na+]>C1COCC1>[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([O:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)[CH3:24])[CH3:20]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CCOC(=O)[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.77 g), THF (15 mL), 2-hydroxy-(2S)-propanoic acid ethyl ester (0.40 mL) and 60% sodium hydride (0.14 g) to give the subtitle compound as a clear, colourless oil. Yield: 1 g
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:30][NH:31][C:32](=N)[CH:33]([CH3:35])[CH3:34]>>[CH:33]([C:32]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][CH2:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)[O:30][N:31]=1)([CH3:35])[CH3:34]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(COC3CCN(C#N)CC3)cn2)c1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC(OCc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-4 using 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)methoxy) piperidine-1-carbonitrile (intermediate 38) and N-hydroxy-isobutyramidine (0.010 g, 5.8%).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[CH:17](O)=O.C=O>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: Cc1ccncc1OC[C@@H]1CCCN1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: Cc1ccncc1OC[C@@H]1CCCN1C

Procedure:
To a 330 mg sample of 4methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (from Example 27 above) was added a solution of formic acid/ formaldehyde (1:2,2 mL). The mixture was heated at reflux for 5 hours, and the volatiles were removed by evaporation. The residue was dissolved in 1 mL of 20% NaOH. The solution was extracted with CH2Cl2 (3X), then the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography over silica gel to afford 295 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.17 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.06 (d, J=5.5 Hz, 1H), 4.07 (dd, J=3.3, 10.6 Hz, 1H), 3.98 (dd, J=7.4, 10.6 Hz, 1H), 3.15-3.08 (m, 1H), 2.76-2.68 (m, 1H), 2.53 (s, 3H), 2.38-2.25 (m, 1H), 2.26 (s, 3H), 2.12-1.67 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=2)[N:3]=1.[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=2)[CH2:22][CH2:21]1>C(O)C>[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH:28][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=4)[N:3]=3)[CH:24]=2)[CH2:22][CH2:21]1
Reactant: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Cl)n2)cc1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Product: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 85 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
A mixture of 2-(4-(4-chloro-5-nitropyrimidin-2-yl)phenyl)acetonitrile (55 mg, 0.2 mmol, 1 equiv.) and 5-cyclopropyl-1H-pyrazol-3-amine (37 mg, 0.3 mmol, 1.5 equiv.) in ethanol (2 ml) was stirred at 85° C. for 15 h. Ethanol was remove under reduce pressure. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1) to afford 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidin-2-yl)phenyl)acetonitrile (45 mg, 62%) as solid. The compound was determination by LC-MS (LC-MS (m/z)=362.1 [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccc2)c1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then benzyl bromide (228 μl). The mixture was stirred at room temperature for 40 minutes. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p 75-76° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:20]N1C(=O)CCC1=O.O>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)cc(C(N)=O)c2C1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution under nitrogen of 21.1 g (79.6 mmol) of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 600 ml of dichloromethane, cooled to −40° C., is added dropwise a solution of 10.6 g (79.6 mmol) of N-chlorosuccinimide in 200 ml of dichloromethane over about 40 minutes. Stirring is continued for 6 hours at a temperature of −40° C., 150 ml of water are then added and the reaction medium is allowed to warm to room temperature. The product is isolated by filtration and is washed with water to give 17.5 g of tert-butyl 8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a whitish solid after drying under reduced pressure at 40° C. in the presence of phosphorus pentoxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH:23]=2)=[CH:8][C:9]=1[N:10]([C:37]([C@H:34]1[CH2:35][CH2:36][C@H:31]([CH3:30])[CH2:32][CH2:33]1)=[O:38])[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1NC1CCC(n2cncn2)CC1
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1

Procedure:
5-(4,4-Dimethyl-cyclohex-1-enyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino) thiophene-2-carboxylic acid methyl ester (0.800 g, 2 mmol) was acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described (example 1, step II) to give 5-(4,4-Dimethyl-cyclohex-1-enyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.640 g, 60%).