Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH3:11][N:12]1[C:16]([OH:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][N:12]1[C:16]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=2)=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Cc1cc(Br)nc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 74.4 %

Procedure:
7.6 g 2-bromo-6-cyano-4-methylpyridine, 9 g 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and 9.7 g potassium carbonate were mixed in 30 ml N,N-dimethylformamide and heated to reflux for 5 hours. After cooling, the reaction mixture was poured into 300 ml water and the aqueous layer extracted three times each with 100 ml ethyl acetate. The combined extracts were dried with anhydrous magnesium sulphate and the solvent removed in vacuo. Purification by silica gel column chromatography using hexane/ethyl acetate 7:3 afforded 8.1 g (50%) of the title compound as a pale brown solid of melting point 88° C.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[S:13][S:12][C:11](=S)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.O1CCCC1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(N(CC)CC)C>[CH3:2][C:1]([NH:5][C:6]([N:8]=[C:9]1[N:10]=[C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[S:12][S:13]1)=[O:7])([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)NC(=O)Nc1nc(=S)ss1
Solvent: CI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2nc(=NC(=O)NC(C)(C)C)ss2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.63 parts of 1-t-butyl-3(-3-thioxo-3H-1,2,4-dithiazol-5-yl)urea and 1.42 parts of methyl iodide in 50 parts of tetrahydrofuran was stirred for 1 hour at room temperature and refluxed with stirring for 1 hour. After cooling to room temperature 3.0 parts of triethylamine and 1.0 parts of N-methyl piperazine were added to the suspension and the mixture was stirred at room temperature overnight. The mixture was filtered to remove triethylamine hydroiodide and the solvent was removed from the filtrate under reduced pressure. The filtrate residue was triturated with water and recrystallized from methanol to afford 1.0 part of the title compound, m.p. 169°-172°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12]C(=O)C(=O)C)[CH:3]=1.[CH3:18][C:19]([O-:21])=O.[Na+].[CH3:23]C(O)=O>CC(OC(C)=O)=O.O>[C:19]([O:8][C:6]1[C:5]2[CH:9]=[CH:10][C:2]([CH3:23])=[CH:3][C:4]=2[O:11][CH:12]=1)(=[O:21])[CH3:18]
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: CC(=O)C(=O)COc1cc(Cl)ccc1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1coc2cc(C)ccc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-2-(2,3-dioxobutoxy)benzoic acid (5 g, 19.48 mmol) in HOAc (80 mL) and Ac2O (100 mL) was added NaOAc (4.2 g, 51.22 mmol). After stirring for 3 h at 150° C., the resulting mixture was dissolved in water (1000 mL), extracted with ethyl acetate (3×200 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6-methyl-1-benzofuran-3-yl acetate as off-white oil (3.8 g, 85%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][CH:16]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[CH2:30]([N:37]1[CH2:12][CH:13]2[O:17][CH:16]([CH2:15][CH2:14]2)[CH2:18]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CCC(C2)O3)cc1

Procedure:
112 g (250 mmol) of 2,5-anhydro-3,4-dideoxy-1,6-bis-O-[(4-methylphenyl)sulfonyl]-hexitol from step 1 and 90.7 g (840 mmol) of benzylamine in 500 ml of toluene are heated under reflux for 20 hours. The precipitate is then filtered off with suction and washed with toluene. The combined toluene phases are concentrated in a rotary evaporator and distilled in vacuo. After a benzylamine fore-run, the product is obtained.
Reaction SMILES: C(OP(CP(OC(C)C)(=O)OC(C)C)(OC(C)C)=O)(C)C.[C:22]1([P:39]([O:45]C(C)C)(=[O:44])[O:40]C(C)C)([P:29]([O:35]C(C)C)(=[O:34])[O:30]C(C)C)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.BrCCCCCCBr.C(P(OC(C)C)(=O)OC(C)C)(P(OC(C)C)(=O)OC(C)C)CCCCCCC(P(OC(C)C)(=O)OC(C)C)P(OC(C)C)(=O)OC(C)C>C1(C)C=CC=CC=1>[C:22]1([P:39]([OH:45])(=[O:40])[OH:44])([P:29]([OH:34])(=[O:30])[OH:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)CCCCCC1
Agent: BrCCCCCCBr
Agent: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: CC(C)OP(=O)(OC(C)C)C(CCCCCCC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Product: O=P(O)(O)C1(P(=O)(O)O)CCCCCC1

Procedure:
Using the same procedure as in Example I, tetraisopropyl methane diphosphonic acid was converted to tetraisopropyl cycloheptane-1,1-diphosphonate by reaction with 1,6-dibromohexane at 80° C. for 18 h. 31P NMR (toluene) indicated that the reaction solution contained a mixture of the desired tetraisopropyl cycloheptane-1,1-diphosphonate (25.3 ppm) and octaisopropyl octane1,1,8,8-tetraphosphonate (22.1 ppm). The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel, and the desired ester was hydrolyzed using 6N refluxing hydrochloric acid as in Example I.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:32]>CO>[ClH:32].[ClH:32].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (38 mg, 0.075 mmol, from Step A), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 34 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ 2.59-2.66 (m, 2H), 2.92 (m, 2H), 3.89-4.16-4.22 (m, 5H), 4.70-4.84 (m, 2H), 5.42 (m, 1H), 6.86 (m, 1H), 7.06 (m, 1H), 7.24 (m, 1H). ESI-MS 407 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])(O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1CCC(O)(c2cccc(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC1CC=C(c2cccc(F)c2F)CC1
Temperature: 30 °C
Yield: 58.8 %

Procedure:
The compound (23) (130.1 g), p-toluenesulfonic acid (1.3 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (500 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder, and dried, giving 71.6 g of 4-butoxy-(2,3-difluorophenyl)cyclohexene (24). The compound (24) obtained was a colorless oil, having the boiling point at 131 to 132° C./3 mmHg, and the yield based on the compound (6) was 66.5%.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]=[C:16]=[O:17].C([Li])CCC>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:16]([NH:15][C:9]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])=[O:17])=[CH:5][N:6]=1
Reactant: Clc1nccs1
Reactant: Cc1cccc(Cl)c1N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(Cl)s1

Procedure:
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: CCOCC.[C:6](Cl)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]=[CH:18][CH3:19].[CH:22]1([CH2:25][CH2:26][CH2:27][OH:28])[CH2:24][CH2:23]1>N1C=CC=CC=1>[C:6]([O:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:24][CH2:23]1)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]=[CH:18][CH3:19]
Reactant: OCCCC1CC1
Reactant: CC=CC=CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC=CC=CCCCCCCCCC(=O)OCCCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 30 ml. anhydrous ether and 0.23 g. 10,12-tetradecadien-1-oyl chloride is added 0.1 g. 3-cyclopropyl-1-propanol. The mixture is cooled to 0° and 0.5 ml. pyridine is added. The reaction mixture is stirred for 1 day at room temperature and then is worked up following the procedure of Example 3 to yield 3-cyclopropylpropyl 10,12-tetradecadienoate.
Reaction SMILES: [N:1]1([C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[O:7].C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:23]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([N:1]3[CH2:5][CH2:4][CH2:3][C@H:2]3[C:6]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-1-((9H-fluoren-9-yl)methyl) 2-(2-(tert-butoxy)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (Fmoc-Pro-HOGly-OtBu) (Compound SP631) (6.40 g, 14.2 mmol) in methylene chloride (29 mL) was mixed with triisopropylsilane (7.29 mL, 35.4 mmol) and trifluoroacetic acid (14.2 mL, 184 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidin-2-carbonyl)oxy)acetic acid (Fmoc-Pro-HOGly-OH) (Compound SP632) (5.6 g, 14.2 mmol, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([I:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (prepared as in Example 2, Part A) and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as in Example 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 691.35; m/z found, 689/691 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (s, 1H), 8.36 (dd, J=7.1, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.08 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.36-7.30 (m, 2H), 7.14 (d, J=2.0, 1H), 6.95 (d, J=8.3, 1H), 6.90 (dd, J=8.2, 2.0, 1H), 6.53 (d, J=7.0, 1H), 4.94 (q, J=5.6, 1H), 3.82 (s, 3H), 3.25-3.10 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[BH4-].[Na+].O.[OH-].[Na+]>C(O)C.ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C1CCN(CC2CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: OC1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a cold (0° C.) solution of 1-cyclopropylmethyl-piperidin-4-one (314 mg, 2 mmol, 1.0 eq.) in ethanol (4 mL) was added sodium borohydride (61 mg, 2 mmol, 0.75 eq.). The reaction mixture was stirred 16 h at room temperature. Water, sodium hydroxide and dichloromethane were added and the reaction mixture was stirred 2 h at room temperature. The aqueous layer was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered then concentrated to dryness in vacuo to yield 160 mg (50%) of the tide compound as colorless oil, witch was used in the next step without further purification. MS (m/e): 156.3 (MH+, 100%).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[O:14][C:13](/[CH:12]=[CH:11]/[C:10]2[CH:9]=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=2)=[N:15][N:16]=1
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(/C=C/c2nnc(N)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Cyanogen bromide (0.7 g, 0.0067 mole) is added to a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid, hydrazide (1.9 g, 0.0067 mole) and sodium bicarbonate (0.56 g, 0.0067 mole) in dioxane (10 ml)/water (10 ml). The resulting mixture is stirred two hours at room temperature. The solution is concentrated to half volume in vacuo and the residue diluted with water. The resulting solid is filtered and recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor., 52%) of (E)-4-[2-(5-amino-1,3,4-oxadiazole-2-yl)ethenyl]-2,6-bis(1,1-dimethylethyl)phenol after drying in vacuo at room temperature, mp 221° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-pyridylethylmercaptan and DBU in DME. ES-MS m/e (%): 324 (M+H+, 100).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Yield: 105.1 %

Procedure:
A mixture of 1-benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (528 mg, 1.66 mmol) prepared in Reference Example 96 and 10% palladium/carbon (50 mg) in acetic acid (5 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, and the mixture was washed with water, 10% sodium hydroxide aqueous solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenyl)piperidine (400 mg, quantitative) as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]([CH3:16])([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>ClCCl.CN(C=O)C>[Cl:2][C:13](=[CH2:14])[C:8]([CH3:16])([CH3:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)(C)C(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(Cl)C(C)(C)C(=O)OC
Temperature: 0 °C

Procedure:
To a suspension of PCl5 (161 g, 0.772 mol) in dichloromethane (600 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (52 g, 0.361 mol, crude from last step) at 0° C., followed by the addition of approximately 20 drops of dry DMF. The mixture was heated at reflux overnight. After cooling, the reaction mixture was slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (300 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 solution and dried over anhydrous Na2SO4. The solvent was evaporated to give the product, methyl 3-chloro-2,2-dimethylbut-3-enoate which was used without further purification (47 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][CH:9]([CH2:14][O:15][CH3:16])[CH2:10][CH2:11][O:12][CH3:13].[N:19]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[Cl:18][C:3]1[C:2]2[N:1]=[N:19][N:8]([C@H:9]([CH2:14][O:15][CH3:16])[CH2:10][CH2:11][O:12][CH3:13])[C:7]=2[CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: COCCC(COC)Nc1cc(C)nc(Cl)c1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COCC[C@@H](COC)n1nnc2c(Cl)nc(C)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-amino-2-chloro-6-methyl-4-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (4.1 g, 14.98 mmol) was dissolved in a mixture of CH2Cl2 (40 mL) and 50% acetic acid (40 mL) and cooled to 0° C. in an ice bath. To that a solution of NaNO2 (1.84 g, 26.86 mmol) in water (10 mL) was added dropwise and the reaction was stirred at 0° C. for 30 min and at 25° C. for 1.5 h. Then the acetic acid was neutralized with solid NaHCO3 and water (80 mL) was added. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were combined and washed with brine (50 mL), dried and stripped in vacuo. The residue was chromatographed on silica gel (40% EtOAc/hexanes eluent) to give the product (4.05 g, 56% overall for the eight steps). NMR(CDCl3)d 7.25 (s, 1H), 5.04-5.13 (m, 1H), 3.98 (dd, 1H, J1=9.9 Hz, J2=8.4 Hz), 3.84 (dd, 1H, J1=10.2 Hz, J2=4.4 Hz), 3.39 (dt, 1H, J1=9.9 Hz, J2=4.8 Hz), 3.25 (s, 3H), 3.17 (s, 3H), 2.91 (dt, 1H, J1=9.5 Hz, J2=4.0 Hz), 2.68 (s, 3H), 2.22-2.6 (m, 2H).
Reaction SMILES: [N:1]1([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].[OH-].[Na+]>O>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-:23])=[O:22])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN1CCCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of compound 3 (0.87 g, 4.285 mmol) in con. H2SO4 (10 mL) was treated with fuming HNO3 (0.2 mL, 4.285 mmol, 90%) drop wise over a period of 10 min. at 0° C. and was stirred at same temperature for additional 20 min. The reaction was diluted with water (50 mL), basified to pH ˜10 using 2 N NaOH solution and product was extracted into CH2Cl2 (3×20 mL). The combined organic layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5 to obtain compound 4 (0.85 g, 80%) including some dinitro derivative, which was separated at later stage.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (147) (7.8 mg, 0.031 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (27 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at 60° C. for 1 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (148) (4.2 mg, yield: 34.9%, purity>90%) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](N)=[C:9]([OH:14])[CH:8]=1)[CH3:2].N([O-])=O.[Na+].[ClH:20]>O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:20])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)/C=C/c1ccc(N)c(O)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cl)c(O)c1
Temperature: 25 °C

Procedure:
(E)-3-(4-Amino-3-hydroxy-phenyl)-acrylic acid ethyl ester (2.76 g, 13.3 mmol) was suspended in HCl solution (6N, 4 ml), and sodium nitrite solution in water (960 mg, 14 mmol) was added at 0° C. The resulting suspension was added at 0° C. to a solution of copper (I) chloride (2 g, 16 mmol) in concentrated HCl (4 ml). The mixture was slowly warmed to RT and heated to 60° C. for 30 min., shaking occasionally. Then it was cooled to RT, diluted with water and extracted with DCM, which was dried and evaporated. The residue was purified by silica gel column chromatography, eluant petroleum ether/AcOEt 90:10, to give 1.46 g of (E)-3-(4-chloro-3-hydroxy-phenyl)-acrylic acid ethyl ester as a white solid.