Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: C1CCNC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-pyrrolidin-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and pyrrolidine following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: COc1cc2c(cc1Cl)C=CN[C@@H]1Cc3ccccc3[C@@H]21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCN[C@@H]1Cc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
The crude Compound N from step D was dissolved in 20 mL absolute ethanol and treated with 0.12 grams (1.91 mmol) sodium cyanoborohydride. To this was added 0.108 mL glacial acetic acid, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 10 mL 1M HCl and stirred for 30 minutes. The reaction was made basic with 30% NaOH and extracted into 250 mL ethyl actetate. The organic layer was dried (MgSO4) and evaporated to give 350 mg (53%) of trans-5,6,7,7a,8,12b-hexahydro-2-methoxy-3-chlorobenz[d]indeno[2,1-b]azepine (Compound P) as an oil, 200 MHz NMR (CDCl3) d 3.60-3.85(m,3H), 3.10-3.40(m,4H), 3.71(s,3H), 4.54(d,1H,J=8 Hz), 7.07(s,1H), 7.16(s,1H), 7.20-7.40(m,4H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12]C(=O)C)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5]([NH2:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of the acetamide from step (b) above (4.5 g, 14 mmol) in MeOH (8 mL) was added aqueous 3N NaOH (50 mL) at room temperature. The reaction mixture was stirred at 90° C. for 2 h, cooled to room temperature and extracted with EtOAc (4×50 mL). The combined organic extracts were washed with 1% aqueous HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (15% EtOAc/hexane) to give the title compound as a yellow solid. MS (ESI, neg. ion) m/z: 282.9 (M−1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)=[N:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)=[N:2]1
Reactant: CCOC(=O)c1cn2cc(-c3nc[nH]n3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3nc[nH]n3)ccc2n1
Yield: 83.5 %

Procedure:
320 mg of ethyl 6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 238 mg of 6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of an off-white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][P:9](=[O:20])([O:15][Si](C)(C)C)[O:10][Si](C)(C)C)(=[O:4])[CH:2]=[CH2:3]>CO>[C:1]([O:5][CH2:6][CH2:7][CH2:8][P:9](=[O:10])([OH:20])[OH:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CO
Product: C=CC(=O)OCCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Di(trimethylsilyl) 3-acryloyloxypropylphosphonate (40 g; 0.118 moles) is dissolved in MeOH (130 ml). The solution is stirred at room temperature for 2 hours. The solvent is vacuum distilled on a rotary evaporator to afford the product as a highly viscous, colorless oil, which solidified after a few days upon storage (22.7 g; yield 99%). 1H NMR (DMSO-d6, δ ppm) 1.78-2.00 (m, 4H, CH2—CH2—P), 4.20 (t, 2H, CH2—O), 4.91 (s, 2H, (HO)2—P), 5.94 (dd, 1H, CH═), 6.16 (dd, 1H, CH═), 6.39 (dd, 1H, CH═). 31P NMR (DMSO-d6, δ ppm) 31.71.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 244 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(cis-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 249.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.87 min, m/z=478.1 [M+H]+, m/z=476.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=11.00, 4.40 Hz, 2H) 3.26 (dd, J=10.64, 5.26 Hz, 2H) 3.94-4.02 (m, 2H) 4.88 (d, J=4.65 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:24]=[CH:25][C:18]=12>C(OCC)(=O)C>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[C:18]2[CH:25]=[N:24]1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-amino-phenol (0.251 g, 2.3 mmol, 1.1 eq) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.13, 5.4 mmol, 2.7 eq). After 10 minutes 4-Chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.1 mmol, 1.0 eq.) was added and the reaction was allowed to warm up to room temperature. After stirring at room temperature for 1 hour the reaction mixture was diluted with ethyl acetate (50 ml) and Was washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, and (1×) brine. The organic layer was dried over sodium sulfate and the solvent removed to give 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine as a yellow solid (570 mg, 87%). 1H NMR (400 MHz, CDCl3): 8.56(s, 1H), 7.75 (s, 1H), 6.97 (d, 2H), 6.64 (d, 2H), 5.96 (dd, 1H), 5.21 (s, 2H), 3.96 (d, 1H), 3.72 (m, 1H), 2.42 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.57 (m, 2H); MS (ESI) for C16H17N5O2: 312 (MH+).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[IH:12].CS[C:15]1[NH:16][CH2:17][CH2:18][N:19]=1>CO>[IH:12].[NH:19]1[CH2:18][CH2:17][N:16]=[C:15]1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2]1
Reactant: CSC1=NCCN1
Reactant: C1CCC2(CC1)CCNCC2
Agent: I
Solvent: CO
Product: C1CCC2(CC1)CCN(C1=NCCN1)CC2
Yield: 41.4 %

Procedure:
3-Azaspiro[5,5]undecane (0.38 g, 2 mmol) and 2-methylthio-2-imidazoline hydroiodide (0.44 g, 1.8 mmol) was refluxing in CH3OH overnight, concentrated in vacuo and purified by flash chromatography to give yellow oil (0.26 g, 65% yield). 1H NMR (360 MHz, CDCl3) δ 8.27 (br s, 2H), 3.72 (s, 4H), 3.39 (t, J=5.83 Hz, 4H), 1.50 (t, J=5.94 Hz, 4H), 1.47-1.44 (m, 10H); 13C NMR (90 MHz, CDCl3) δ 159.48, 43.39, 42.73, 36.02, 35.26, 30.83, 26.65, 21.61. 21.49; ESI-MS: Calculated for C13H24IN3 (M−I)+ 222.3, Found: 222.5.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:4]1[CH:3]=[C:2]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(N2CCCC2)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 95.7 %

Procedure:
A mixture of methyl 4-fluoro-2-[3-(tert-butoxycarbonylamino)propoxy]benzoate (8.148 g, 25 mmol) and pyrrolidine (20.87 mL, 250 mmol) was purged with nitrogen and heated to 80° C. for 3 hours. The reaction was concentrated in vacuo. After diluting with EtOAc, the mixture was cooled to 0° C., acidified with satd citric acid, and extracted with EtOAc. The organic layer was washed with satd citric acid and water, dried (Na2 SO4), and concentrated. The resulting residue was absorbed onto silica gel and chromatographed (20% EtOAc/hexane to 35% EtOAc/hexane). The resulting product was triturated with Et2O/hexane to give the desired product as a white solid (9.05 g, 99%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[C:10]([NH:25]C(=O)C(F)(F)F)=[C:11]([O:23][CH3:24])[C:12]([F:22])=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[CH3:15])#[N:8]>CO>[NH2:25][C:10]1[C:11]([O:23][CH3:24])=[C:12]([F:22])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([CH3:15])[C:9]=1[C:7]#[N:8]
Reactant: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Aqueous 20% (w/v) potassium carbonate solution (9.0 ml, 13.0 mmol) was added to a methanol (9 ml) suspension of N-(5-cyano-2-fluoro-3-methoxy-6-methylbiphenyl-4-yl)-2,2,2-trifluoroacetamide (I-37) (400 mg, 1.14 mmol), followed by stirring at 70° C. for 16 hours. The reaction liquid became uniform with temperature elevation. The reaction liquid was cooled to room temperature, methanol was evaporated away under reduced pressure, water was added to the residue, followed by extraction twice with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After nitration and concentration under reduced pressure, the entitled compound (266 mg, 91%) was obtained as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.[C:30]([OH:49])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C=O.[C:52]([O-])(=[O:70])CCCCCCCCCCCCCCCCC.[Li+]>C1COCC1>[OH:70][CH2:52][CH:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:30]([OH:49])=[O:48]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: C=O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCC(CO)C(=O)O
Temperature: -20 °C
Yield: 71 %

Procedure:
Anhydrous THF (327 ml) and 19.7 g (0.195 mole) of diisopropylamine are added to a dry three-neck flask purged with nitrogen and maintained under a nitrogen atmosphere. After cooling the mixture to -20° C., 123 ml of n-butyllithium in hexane (1.6 M) (0.195 mole) is added slowly to prevent the temperature from exceeding 0° C. and then 32.2 ml of anhydrous HMPA (0.18 mole) is added. A solution of 23.0 g of stearic acid (0.081 mole) in 165 ml of THF is added dropwise with stirring while maintaining the reaction temperature below 0° C. A milky white suspension results after the addition of stearic acid. The reaction mixture is brought to about 40° C. by using a warm water bath. The suspension changed to a clear solution as the temperature gradually reaches 40° C. This system is then connected to a formaldehyde generating system. Paraformaldehyde (16.4 g) is heated in a three-neck flask at 180°-200° C. to generate formaldehyde and the formaldehyde vapors are carried by a stream of nitrogen over the surface of the stirred solution of α-lithiated lithium stearate prepared previously. The reaction is terminated after complete depolymerization of paraformaldehyde (2 to 21/2 hrs.). The reaction solution is cooled in an ice bath and neutralized with hydrochloric acid until acidic. The organic layer is separated and then concentrated under reduced pressure to remove most of the THF solvent. The resulting oily residue is dissolved in 2 liters of ether and washed three times with 10% hydrochloric acid and then twice with water. The ether layer is dried over Na2SO4 and the solvents removed under reduced pressure to give 22.4 g (92%) of crude product which is recrystallized once from acetone to give 17.3 g (71% yield) of α-hydroxymethylstearic acid, m.p. 62°-67° C. This material is used for the next reaction withouth further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:20][CH:21]=1.CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[N:20][CH:21]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)OCC
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of diethyl malonate (0.704 mL, 4.64 mmol) in DMF (2 mL) was added dropwise to a suspention of NaH (200 mg, 4.64 mmol, 55% in mineral oil) in DMF (4 mL) at 0° C. under argon. The reaction mixture was stirred for 30 min and a solution of 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin (1.5 g, 3.86 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. EtOAc was added and the solution was washed with water and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 3:2) gave 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-malonic acid diethyl ester (0.87 g, 40%).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[C:12]([CH3:14])([CH3:13])[C:11]1([CH3:15])[CH2:10][CH2:9][C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)CCC=C(C)CCC(C)=C(C)C
Solvent: ClCCl
Product: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g. of 6,9,10-trimethyl-undeca-5,9-dien-2-one in 2,000 ml. of methylene chloride, there was added while cooling with ice, 100 g. of m-chloroperbenzoic acid. The resulting mixture was allowed to stand while constantly stirring at room temperature for 1 hour. The resulting mixture was diluted with 1,000 ml. of methylene chloride. The resulting solution was washed with ice-cold 1N sodium hydroxide solution and with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was fractionally distilled under high vacuum. There was obtained 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one; b.p. 89°-91°C./0.07 mmHg; nD20 = 1.4656.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=O)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[S:22])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2ccccc2)n1
Solvent: c1ccncc1
Product: Cn1cc(-c2ccccc2)c(=S)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1 g. portion of the product of Example 4 was dissolved in 10 ml. of pyridine and heated under reflux for 4 hours with 1 g. of P2S5. The solution was then poured into ice water and stirred for 30 minutes. The precipitate was recovered by filtration and crystallized from hexane-isopropyl alcohol. The yield was 1 g. of 1-methyl-3,5-diphenyl-4(1H)-pyridazinethione, m.p. 122°-23°C., which was identified by infrared, nuclear magnetic resonance and ultraviolet analyses, and by mass spectrometry.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)([O:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:56][CH2:57]O)[CH:50]=1.C(O)=CC>O1CCCC1>[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:56][CH2:57][O:13][C:14]2[CH:15]=[C:16]([C:20]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)([O:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH:50]=1
Reactant: OCC=Cc1cccnc1
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Agent: CC=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(OC)(c1cccc(OCC=Cc2cccnc2)c1)c1nccs1
Reaction time: 2 h
Yield: 29.8 %

Procedure:
Diethyl azodicarboxylate (0.38 ml) was added dropwise to a mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.37 g), triphenylphosphine (0.57 g), 3-(3-pyridyl)prop-2-en-1-ol (0.27 g) and tetrahydrofuran (7 ml) which had been cooled to 0°-5° C. in an ice-bath. The mixture was stirred at this temperature range for 2 hours and then at ambient temperature for 4 hours. Further portions of diethyl azodicarboxylate (0.1 ml), triphenylphosphine (0.14 g) and the propenol (0.045 g) were added and the mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (40 ml) and dilute aqueous hydrochloric acid (40 ml). The aqueous layer was separated and basified by adding potassium carbonate portionwise. The resulting solution was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (2/3 v/v) to give 2-[1-[3-(3-(3-pyridyl)prop-2-en-1-yloxy)phenyl]-1-methoxypropyl]thiazole as a colourless oil (0.162 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]2[CH:22]=[CH:23][S:24][C:14]=12.C(N(CC)CC)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:13]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]4[CH:22]=[CH:23][S:24][C:14]=34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1CCC2(CC1)OCCO2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-amine (from J&W PharmLab, 0.40 g, 2.5 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.29 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in isopropyl alcohol (4.4 mL) was stirred at 90° C. for 2 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccc3)c2n1C1CC1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), phenylboronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by recrystallisation from EtOAc/cyclohexane to afford 415 as a white solid (10 mg, 15%). LCMS (Method K): RT 4.08 min [M+H]+ 414.08. 1H NMR (CDCl3 400 MHz): δ 8.17 (1H, s), 7.65 (1H, dd, J=8.89, 4.63 Hz), 7.43-7.42 (5H, m), 7.09 (1H, dd, J=10.20, 8.76 Hz), 6.35 (1H, d, J=7.83 Hz), 5.96 (1H, m), 5.32 (2H, s), 2.89-2.83 (1H, m), 1.69 (3H, d, J=6.74 Hz), 0.79 (1H, m), 0.61 (1H, m), 0.47 (1H, m), 0.23 (1H, m)
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=O)=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12.O1C=C[N:26]=C1Cl>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12
Reactant: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Reactant: Clc1ncco1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1sc(C(N)=O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
4,5-Dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b′]dithiophene-6-carboxylic acid (0.50 g) was dissolved in tetrahydrofuran (10 ml); oxazolyl chloride (0.15 ml) and then N,N-dimethylformamide (one drop) were added. After the mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml); concentrated aqueous ammonia (5 ml) was added. After the reaction mixture was stirred at room temperature for one hour, it was poured over water and extracted with chloroform-methanol the organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b′]dithiophene-6-carboxamide (0.28 g, 56%), which was recrystallized from ethanol. Melting point 192-193° C.