Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.O[CH:7]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH2:8][C:9]([CH2:12][Si](C)(C)C)=[C:10]=[CH2:11].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:11]=[C:10]1[C:9](=[CH2:12])[CH2:8][CH:7]2[O:20][CH:19]1[CH:18]1[C:17]2=[C:24]=[CH:23][CH:22]=[CH:21]1
Reactant: C=C=C(CC(O)c1ccccc1C=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CC2OC(C1=C)C1C=CC=C=C21
Temperature: -78 °C
Yield: 77.2 %

Procedure:
5.2 mL of diethyl ether was added to 2-(1-hydroxy-3-trimethylsilanylmethyl-penta-3,4-dienyl)-benzaldehyde (358 mg, 1.30 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (235 μL, 1.30 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 185 mg of the product (77%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[OH:27]OS([O-])=O.[K+]>C(O)(=O)C.O>[CH3:1][S:2]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)=[O:27]
Reactant: CSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 2-(methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (2.1 g) in acetic acid (40 mL) was added a solution of oxone (registered mark) (4.02 g) in water (8 mL). The reaction mixture was stirred at room temperature for 2 hr, water was added thereto, and the precipitate was collected by filtration to give the title compound (1.68 g).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][N:36]([CH3:38])[S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1
Product: CN(C)S(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N,N-dimethyl-benzenesulfonamide [CAS 6274-18-6; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 540.4 [(M+H)+]; mp 197° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH:24]=O)[C:17]2=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[C:23]1(/[CH:24]=[C:2]2\[N:3]=[C:4]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:13][C:1]\2=[O:12])[C:17]2[C:18](=[CH:19][CH:14]=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2)=N/C1=C\c1cccc2ccccc12
Temperature: 80 °C

Procedure:
A solution of hippuric acid (4.0 g, 1.0 eq.) was added to a solution acetic anhydride (10 mL), 1-naphthylaldehyde (3.84 g, 1.1 eq.) and sodium acetate (2.21 g, 1.2 eq.). The reaction mixture was then heated at 80° C. for 2 hours, then cooled to room temperature, filtered, and washed with acetic anhydride. After air drying, the solid was washed back with water and air-dried overnight to give the desired compound.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:30][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:5]1
Reactant: COc1cccc(CCN2CCCC[C@@H]2CO)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCN2CCCC[C@@H](Cl)C2)c1
Reaction time: 18 h

Procedure:
(R)-2-Hydroxymethyl-1-(3-methoxyphenethyl)piperidine (322 mg, 1.28 mmol) was dissolved in 10 ml of dichloromethane. Triethylamine (170 mg, 1.68 mmol) and methanesulfonyl chloride (192 mg, 1.68 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 18 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(3-methoxyphenethyl)homopiperidine in the form of a light yellow oil (182 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:16]2([OH:19])[CH2:17][CH2:18][O:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: O=C1CCOC1
Reactant: Brc1cnc(I)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ncc(Br)cn2)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
5-Bromo-2-iodopyrimidine (10 g, 35.1 mmol) was dissolved in dry toluene (100 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 14.7 mL) was added dropwise and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxolan-3-one (2.97 mL, 38.6 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed successively with water and brine, then dried over magnesium sulphate. The solvent was removed under reduced pressure to afford a dark yellow oil. The crude material was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0-100% ethyl acetate in heptanes, to afford the title compound (2.15 g, 25% at 86% purity) as a yellow oil. δH (500 MHz, DMSO-d6) 9.01 (s, 2H), 5.66 (s, 1H), 3.99-3.93 (m, 2H), 3.88-3.77 (m, 2H), 2.46 (dt, J 12.6, 8.9 Hz, 1H), 2.16 (ddd, J 12.6, 6.4, 3.5 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O:20]1[CH2:27][CH:21]1[CH2:22][NH:23][CH:24]([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)C.C(OC(C)C)(C)C>[OH:20][CH:21]([CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])[CH2:27][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)NCC1CO1
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 13.2 %

Procedure:
A solution of 3-hydroxy-2-phenyl-isoindolin-1-one (6.75 g.) in anhydrous dimethylformamide (20 cc.) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (1.48 g.) in anhydrous dimethylformamide (20 cc.). When the evolution of gas has ceased, 2,3-epoxy-1-isopropylamino-propane (3.8 g.) is added whilst keeping the temperature at about 5° C. After the end of the addition, stirring is continued for a further 24 hours at a temperature of about 20° C. and then the reaction mixture is poured into ice-water (250 cc.). The insoluble oily product is extracted with methylene chloride (3 × 100 cc.). The solution obtained is dried over sodium sulphate and then concentrated to dryness under reduced pressure. The oily residue is taken up in diethyl ether (50 cc.) and the insoluble product is filtered off and then washed with diethyl ether (30 cc.). The filtrate is then extracted with 0.5N hydrochloric acid (60 cc.). The acid solution obtained is washed with diethyl ether (20 cc.) and then rendered alkaline by the addition of 1N sodium hydroxide solution (30 cc.). The insoluble oily product is extracted with diethyl ether (2 × 50 cc.) and the solution obtained is dried over sodium sulphate and then concentrated to dryness under reduced pressure. The oily product obtained is dissolved in a mixture of diethyl ether and di-isopropyl ether (1/1 by volume; 20 cc.), and the product which crystallises is filtered off and then washed with a mixture of diethyl ether and di-isopropyl ether (1/1 by volume; 5 cc.). After drying, 3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-isoindolin-1-one (1.35 g.), melting at 92° C., is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[CH:31]=[CH:30][C:29]=3[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[CH:31]=[CH:30][C:29]=3[S:37](=[O:40])(=[O:39])[NH:38][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[Cl:41])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-4-[(2'-sulfamoyl-5'-propylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step E) and 2-chlorobenzoic acid (2.0 equivalents), CDI (2.0 equiv), and DBU (2.0 equiv) according to the procedure of Example 51 to give an 86% yield of the desired material as a cream-colored solid after flash chromatography, mp 67°-69° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 711 (M+1)+.
Reaction SMILES: CC(C(N[C@@:8]([CH3:20])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9](O)=[O:10])=O)(C)C.ClC1C=CC([NH2:26])=CC=1>>[CH3:20][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9]([NH2:26])=[O:10]
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc([C@](C)(NC(=O)C(C)(C)C)C(=O)O)cc1
Product: COc1ccc(C(C)C(N)=O)cc1

Procedure:
(S)-α-[N-[(1,1-Dimethylethyl)carbonyl]amino]-α-methyl-4-methoxybenzeneacetic acid (preparation described in step A of Example 101) was condensed with 4-chloroaniline following the procedure described in step A of Example 99. Pure (S)-N-(4-chlorophenyl)-α-[N-[(1,1-dimethylethyl)carbonyl]]-amino!-α-methyl-4-methoxybenzeneacetamide, obtained after chromatography on silica gel using 20% EtOAc/hexane as eluant, was converted to the title compound following the procedure described in step A of Example 98.
Reaction SMILES: N1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>ClC(Cl)C>[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=[N:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cnccn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A 1.62 ml quantity of pyridine was dissolved in 60 ml of dichloroethane. To the solution was added 0.89 g of aluminum chloride powder, and the mixture was refluxed with heating for 15 minutes. Then to the mixture were added 2.20 g of 2,6-di-tert-butyl-1,4-benzoquinone and 0.95 g of aminopyrazine, and the mixture was refluxed under heating for 17.5 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dicloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 1.73 g of Compound 1a.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:51]([CH:56]=O)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:51]([CH:56]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1ncccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (4.42 g, 9.00 mmol) was suspended in THF (50 ml) under argon. Lithium bis-(trimethylsilyl)amide (1M in THF, 10.8 ml) was added and the deep orange reaction was stirred at ambient temperature for 1 hour. A solution of 3-benzyloxy-2-pyridinecarbaldehyde (2.0 g, 9.4 mmol) in THF (20 ml) was added and the reaction was stirred at ambient temperature for 2 hours 30 minutes. The reaction was partitioned between EtOAc/water, the aqueous phase was extracted with EtOAc, the organic layers were combined, dried (MgSO4) and evaporated. The residue was purified by chromatography (EtOAc/CH2Cl2) to give methyl 4-[2-(3-benzyloxy-2-pyridyl)ethenyl]benzoate as a yellow oil. (3.01 g) .
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][S:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)([CH3:10])[CH3:9]
Reactant: CC(C)OCCC=CCCl
Reactant: SCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)OCCC=CCSCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
8.1 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene are added dropwise at 20-25° during the course of 10 minutes and while stirring to a solution of 7.9 g (0.05 mol) of 4-chloro-benzylmercaptan and 5.6 g (0.05 mol) of potassium tert.butoxide in 150 cc of tert.butanol. The solution which is rendered turbid during the addition is stirred at 60° during the course of 1 hour and is then cooled and filtered. The solvent is distilled off at reduced pressure, the residue is dissolved in ether and the ether solution is washed with saturated salt solution. The ether phase is dried with sodium sulphate and then the ether is distilled off and the residue is chromatographed on silica gel with chloroform. The 4-[(5-isopropoxy-2-pentenylthio)-methyl]-chlorobenzol is obtained as colourless oil having a B.P. of 110°-112°/5.10-4 mm. nD20 = 1.5391.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:16]([CH3:18])=[CH:15][C:14](=[O:19])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCSc1nnc(N)s1
Solvent: O
Product: CCCCCCSc1nn2c(=O)cc(C)nc2s1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Seven (7.0) grams of the thus obtained 2-amino-5-hexylthio-1,3,4-thiadiazole and 4.3 g of ethyl acetoacetate were mixed with 8 g of polyphosphoric acid, and the mixture was heated to 130°-150° C. and stirred for 30 minutes. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by developing on a silica gel column, and eluting with an ethylacetate/n-hexane (1:1) mixture, and thus 7.5 g of 2-hexylthio-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Refraction index nD20 : 1.6003. Yield 82%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:19]#[N:20].[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)#[N:20]
Reactant: N#Cc1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Cl
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Nc1ccc2ncccc2c1
Reaction time: 20 h
Yield: 13.5 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-2-phenylacetamide (81 mg, 0.281 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-2-phenylacetamide (15 mg).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:28][C:25]3[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Reactant: Cc1ccc(N)cn1
Product: COc1cccc(CNc2cccn3nc(Nc4ccc(C)nc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-(6-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 6-methyl-pyridin-3-ylamine (41.91 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (8.55 mg, 7%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.48 (s, 1H), 8.74 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.96 (d, J=6.7 Hz, 1H), 7.23 (t, J=15.8, 7.7 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.96 (s, 2H), 6.82-6.70 (m, 2H), 6.57 (m, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.71 (s, 3H), 2.40 (s, 3H). MS=361 (MH)+.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:15][CH:16]=[CH2:17])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C=C.C(O)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH2:8]([O:7][CH2:6][CH:5]1[CH2:15][CH2:16][CH:17]=[CH:1][O:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCOC(CC=C)COCc1ccccc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C1=COC(COCc2ccccc2)CC1
Temperature: 120 °C

Procedure:
Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, bis(tricyclohexylphosphine)benzylidine ruthenium(IV) chloride—Grubbs 1 generation catalyst (0.5 g, 0.54 mmol) was added in one portion to a stirred solution of ((2-(allyloxy)pent-4-enyloxy)methyl)benzene (12) (4 g, 17.2 mmol) in toluene (200 mL). The resulting mixture was heated at 50° C. under N2 for 2 hours before isopropanol (18 mL) and NaOH (0.17 g) were added. The mixture was then heated at 120° C. overnight. The solvent was evaporated and the residue was purified over silica gel using Et2O and hexane to give 2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (13).
Reaction SMILES: CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Br[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.[C:45]1([C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH2:61])=[CH:53][CH:52]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:61][C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:51]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:52][CH:53]=2)=[CH:38][CH:39]=1
Reactant: Nc1ccc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A pyrex reaction tube was charged with sodium tert-butoxide (239 mg, 2490 μmol), Pd2(dba)3 (81.4 mg, 88.9 μmol), S-Phos (146 mg, 356 μmol), 1-bromo-4-methoxybenzene (333 mg, 1779 μmol), 4-phenylnaphthalen-1-amine (390 mg, 1779 μmol) and dioxane. The tube was sealed and the mixture was stirred at 100° C. for 2 h. LCMS showed complete conversion to product. The mixture was diluted with DCM and washed with water. The organic portion was dried, filtered and concentrated. The crude material was passed through a plug of silica gel using 50% EtOAc/hex and the filtrate was concentrated to provide the desired product. MS: [M+H]=326.