Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1CNC[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH3:29][N:30]([CH3:67])[C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]3[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][N:48](C(OCC4C=CC=CC=4)=O)[CH2:47]3)=[N:41][C:42]=2[CH2:43][CH3:44])=[C:33]([CH3:66])[CH:32]=1>>[CH3:67][N:30]([CH3:29])[C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]3[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][NH:48][CH2:47]3)=[N:41][C:42]=2[CH2:43][CH3:44])=[C:33]([CH3:66])[CH:32]=1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethyl pyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.98, 6.45, 5.30, 4.51, 4.04, 3.67, 3.52, 3.43, 3.19, 3.12, 2.92, 2.69, 2.51, 2.11, 1.32–1.25, 1.15; IR (liq.) 2971 (s), 2933 (s), 2873 (s), 2345 (b), 1946 (w), 1607 (s), 1565 (s), 1516 (s), 1490 (s), 1395 (s), 1373, 1207, 1163, 1125, 1080 cm−1 HRMS (ESI) calcd for C22H34N6O+H1 399.2872. found 399.2877.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[Na+].[C-:21]#[N:22].[K+].O>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:21]#[N:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A slurry of 1-benzyl-4-piperidone (53.3 g, 0.28 mol), sodium bisulfate (38.5 g, 0.32 mol), potassium cyanide (24.5 g, 0.38 mol) and water (200 mL) was stirred 1 hour and then combined with diethyl ether. The mixture was stirred 1 hour and the ether layer was separated, washed with water (2×) and brine (2×), dried (K2CO3), filtered and concentrated. The residue was crystallized from pentane/diethyl ether (3:1, approximately 400 mL) to give 1-benzyl-4-hydroxypiperidine-4-carbonitrile (45 g) as a crude material.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([NH:6][C@H:7]([C:9]([N:11]1[CH2:25][CH2:24][CH2:23][C@H:12]1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:10])[CH3:8])=[O:5])[CH3:2]>[C].[Pd].CO>[CH2:1]([O:3][P:4]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([NH:6][C@H:7]([C:9]([N:11]1[CH2:25][CH2:24][CH2:23][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1.5 h

Procedure:
A solution of the ester product from part (b) (1.42 g., 3.1 mmole) in 60 ml. of methanol is treated with 10% palladium-carbon catalyst (350 mg.) and hydrogenated in a Parr apparatus at an initial pressure of 45 psi. for 1.5 hours. The mixture is filtered through Celite and evaporated to dryness to give 1-[N-[ethoxy(phenylmethyl)phosphinyl]-L-alanyl]-L-proline as a colorless foam. Tlc (10% methanoldichloromethane) shows a single spot at Rf 0.31.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nc1CN1CCOCC1

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (1.5 g, 6.82 mmol) and potassium carbonate (1.13 g, 8.18 mmol) were taken up in DMF (13 mL) and morpholine (0.59 mL, 6.82 mmol) was added. The mixture was allowed to react at room temperature overnight, at which time water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:30]>C(#N)C.O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][Cl:30])=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)cn1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 3.28 g (9.1 mMol) of {4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 40 ml of acetonitrile, 40 ml of dioxane and 4 ml of SOCl2 is stirred for 1 h at RT. The mixture is dissolved in EtOAc and NaHCO3-solution, the aqueous layer separated off and extracted with EtOAc. The organic layers are washed with NaHCO3-solution, water and brine, dried (Na2SO4) and partially concentrated. The crystallized title compound can be filtered off, elemental analysis for C, H, and N, within 0.4%; of calculated value.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8].C([Li])CCC.C(O)(=[O:36])C.OO>O1CCCC1>[F:28][C:3]1[C:2]([OH:36])=[CH:26][CH:25]=[C:24]([F:27])[C:4]=1[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F
Reactant: CC(=O)O
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(O)c1F
Temperature: -78 °C
Yield: 28 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) ester (3.9 g, 8 mM) was dissolved in tetrahydrofuran (120 mL), trisopropylborate (3.1 g, 17 mM) was added and the mixture was cooled to −78° C. At this low temperature n-butyllithium (7.8 mL, 1.6N) was added drop by drop with stirring. The mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C. Acetic acid (4.4 mL, 50%) was added slowly with stirring (0–5° C.), followed by hydrogen peroxide (1.3 mL, 35%). Stirring continued with cooling for another 45 min and for 1 h at room temperature. The mixture was partitioned between water and diethylether, organic phases were pooled, washed with water, sodium thiosulfate solution (5%), brine and dried with Na2SO4 to yield after evaporation a light yellow oil (4.1 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 0.93 g (28%) of the product as a colorless oil. MS (ISP): 418.2 (M+NH4)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][O:23][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCO
Reactant: O=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCOc1ccc(C=O)cc1
Temperature: -5 °C
Yield: 74.1 %

Procedure:
The compound of Step C 3.61 g (10.9 mmole), 1.53 g (12.5 mmole) 4-hydroxybenzaldehyde, and 3.29 g (12.5 mmole) triphenylphosphine were dissolved in 30 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −5° C. ancl a solution of 1.97 ml (12.5 mmole) diethylcliazodicarboxylate in 10 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +3° C. The bath was removed and the reaction stirred under nitrogen for 3 days. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 5% isopropyl alcohol/hexane. The appropriate fractions were bulked and stripped to give 3.52 g (74%) product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1
Reactant: COC(=O)c1cc(-c2cnc3cc(-c4ccccc4)cc(OC)n23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)O)c3)n12
Temperature: 70 °C

Procedure:
To a solution of methyl 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylate (94 mg, 0.26 mmol) in methanol (10 ml) and water (0.5 ml) was added a 5M aqueous solution of sodium hydroxide (0.50 ml, 2.5 mmol). The reaction mixture was heated to 70° C. After 1 h the reaction mixture was cooled and quenched with a 1N solution of hydrochloric acid (2.5 ml, 2.5 mmol), and then partially concentrated to precipitate yellow solids. The solids were washed with water and dried under vacuum to give 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylic acid. LRMS (ESI) calculated for C19H15N2O3S [M+H]+, 351.1 found 351.0.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:4][CH2:5][CH2:6][C:7](=O)[CH3:8])[CH3:3].[OH-].[K+].[C:13](#[N:15])[CH3:14]>>[CH3:8][C:7]1([CH2:14][C:13]#[N:15])[CH2:6][CH2:5][CH2:4][C:2]([CH3:1])([CH3:3])[O:10]1
Reactant: CC#N
Reactant: CC(=O)CCCC(C)(C)O
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CCCC(C)(CC#N)O1

Procedure:
The distillation residue of the second reaction is again recycled for a third synthesis after adding a further 122.7 g of 94.5% 2-methyl-heptan-2-ol-6-one (0.80525 moles), 5.2853 g of 86% KOH and acetonitrile in the usual ratio. After the reaction, distillation gives 82.0 g of 2,6,6-trimethyl-2-cyanomethyltetrahydropyran (0.49099 moles) in the distillate, together with the unconverted hydroxyketone.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:17]2[C:18]3[O:23][C@@H:22]([CH2:24][OH:25])[CH2:21][O:20][C:19]=3[CH:26]=[CH:27][C:16]=2[S:15][CH:14]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:25][CH2:24][C@@H:22]2[CH2:21][O:20][C:19]3[CH:26]=[CH:27][C:16]4[S:15][CH:14]=[C:13]([Cl:12])[C:17]=4[C:18]=3[O:23]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccc3scc(Cl)c3c2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4scc(Cl)c4c3O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
4-Dimethylaminopyridine (0.26 g) then 4-toluenesulphonyl chloride (0.40 g) were added to a stirred solution of (S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4]-benzodioxin (0.49 g) in dichloromethane (20 ml), and the mixture then stirred at ambient temperature for 24 hours. The resulting solution was poured into water (100 ml) and extracted with dichloromethane (150 ml). The resulting organic solution was then washed successively with saturated copper sulphate solution (2×100 ml) and water (100 ml). The solution was dried over sodium sulphate and the solvent evaporated under reduced pressure to give (S)-9-chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl 4-toluene-sulphonate (0.7 g) as a white solid m.p. 169-70° C.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[OH:13].Br[CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[O:13][CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)s1
Reactant: CCn1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(OCc2ccc(C(=O)c3ccc(Cl)cc3)s2)c(Cl)c1=O
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To 20 ml of N,N-dimethylformamide were added 1.9 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone, 3.2 g of 2-bromomethyl-5-(4-chlorobenzoyl)-thiophene and 1.5 g of potassium carbonate, and the mixture was stirred at 50° to 60° C. for 2 hours. After cooling, the reaction mixture was poured into 50 ml of water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 4.0 g of a crude product. The crude product was recrystallized from 2-propanol to obtain 3.1 g of 4-chloro-5-[{5-(4-chlorobenzoyl)-2-thienyl}-methyloxy]-2-ethyl-3(2H)-pyridazinone, m.p. 168.0°~168.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[O:6]1[C:10]2C=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl.CCOCC>[O:2]1[C:3]2[CH:7]=[CH:8][C:9]([CH:10]=[O:6])=[CH:14][C:13]=2[CH2:12][CH2:1]1
Reactant: c1ccc2c(c1)CCO2
Reactant: COC(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a stirred solution of α,α-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at −40° C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2Cl2 (5 mL) maintaining the temperature at or below −35° C. The mixture was warmed to 0° C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121° C. at 0.3 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:34]([S:46]SC(=N)N)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>C(O)C.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:46][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])=[N:11]1
Reactant: COc1cc(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCSC1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)N=C1Nc1cc(OC)c(Cl)cc1Cl

Procedure:
15.1 g of 1-(2,4,6-trichlorophenyl)-3-(2,4-dichloro-5-methoxyanilino)-5-pyrazolone was dissolved in 500 cc of 80% ethanol (volume ratio of ethanol to water: 4:1), and 2.5 g of potassium carbonate was added. 10.4 g of S-(n-dodecylthio)isothiourea hydrochloride dissolved in 100 cc of ethanol was dropwise added over a period of 10 minutes on a steam bath with stirring under heating, and further, the mixture was stirred under heating. After cooling with flowing water, 300 cc of ethyl acetate was added, followed by washing twice with water. After drying ethyl acetate layer with anhydrous sodium sulfate, sodium sulfate was removed, the solvent was concentrated under reduced pressure, and the residue was crystallized from acetonitrile. The thus-obtained crystal was recrystallized from acetonitrile-ethyl acetate (volume ratio: 10:1) to obtain 18 g of the coupler having a melting point of 100° to 102° C. (conversion rate: 95%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([F:37])=[C:35]([F:36])[C:28]=2[F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1ccc(F)c(F)c1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(F)c(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3,4-trifluorobenzyl alcohol (119 mg; 0.736 mmol), example 72 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:29]3[CH2:30][CH2:31][S:26][CH2:27][CH2:28]3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(C2CCSCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.44 g, 1.2 mmol) in methanol-acetic acid (95:5) (10 mL) was treated with tetrahydrothiopyran-4-one (1.34 g, 11.5 mmol) and sodium cyanoborohydride (4.6 mL of a 1 M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 48 h, then heated at 50° C. for an additional 60 h. After cooling to room temperature, the solvent was removed in vacuo; the resulting residue was redissolved in methanol and directly applied to 5×10 g SCX columns, washed with methanol and eluted with dichloromethane-2 N ammonia in methanol (1:1). The product fractions were concentrated in vacuo and the residue was purified via silica gel chromatography. Elution with ethyl acetate followed by ethyl acetate-methanol (9:1) afforded the title compound (0.46 g, 84%) as a yellow solid, which was further purified via trituration in acetonitrile followed by separation of the yellow mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 4-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 3-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(4-chloro-phenyl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)#[N:33]>>[C:32]([C:34]1[CH:35]=[C:36]([S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)#[N:33]
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: N#Cc1cccc(S(N)(=O)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(C#N)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-cyanobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.26-8.21 (2H, m), 7.86 (1H, d, J=7.9 Hz), 7.68 (1H, t, J=7.9 Hz), 7.46-7.20 (9H, m), 6.01 (1H, br.s), 3.48-3.42 (2H, m), 2.84 (2H, t, J=6.3 Hz), 2.32 (3H, s), 2.21 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:3]([N:5]([C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20](Br)=[C:14]3[N:13]=2)[CH2:8]1)[CH3:6])=[O:4].[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[NH2:1][C@@H:2]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:3]([N:5]([C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:33]4[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:14]3[N:13]=2)[CH2:8]1)[CH3:6])=[O:4]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)C[C@H](N)C(=O)N(C)[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cnn2ccc(N3CC[C@H](N(C)C(=O)[C@@H](N)CC(C)C)C3)nc12
Yield: 17.5 %

Procedure:
(S)-2-amino-N—((S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)-N,4-dimethylpentanamide (220 mg, 0.54 mmol), 2-methoxypyridine-3-boronic acid (164 mg, 1.1 mmol), potassium carbonate (291 mg, 2.15 mmol), Pd(OAc)2 (2 mg, 0.011 mmol) and x-phos (10 mg, 0.022 mmol) were taken up in 2 mL acetonitrile and 1 mL water and heated in a sealed tube at 85° C. for 2 hours. Reaction was then filtered through celite with acetonitrile and DCM reduced in vacuo, then purified on Shimadzu neutral phase prep and product fractions lyophilized to get (S)-2-amino-N—((S)-1-(3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)-N,4-dimethylpentanamide 41.3 mg as 0.5 eq formic salt. 1H NMR (400 MHz, DMSO-d6) δ 8.87-8.97 (m, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.96 (dd, J=2.02, 4.80 Hz, 1H), 7.00-7.11 (m, 1H), 6.51 (d, J=7.83 Hz, 1H), 4.00 (s, 3H), 3.48-3.64 (m, 1H), 3.43 (br. s., 3H), 2.96 (s, 2H), 2.81 (s, 1H), 2.11-2.28 (m, 2H), 1.72-1.89 (m, 1H), 1.19-1.39 (m, 2H), 0.90 (dd, J=1.89, 6.69 Hz, 6H). (ESI) m/z 438 [(M+H)]+, calc'd for C23H31N7O2: 437.5.