Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.ClC1C=CC([C@@H](CNC(C)C)[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=CC=1.[C:50]([O:54][C:55]([NH:57][C@H:58]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)C(O)=O)=[O:56])([CH3:53])([CH3:52])[CH3:51].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@@H:58]([NH:57][C:55](=[O:56])[O:54][C:50]([CH3:52])([CH3:51])[CH3:53])[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=[CH:68][CH:67]=1
Reactant: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CNC(C)C)c4ccc(Cl)cc4)CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0558 mL, 0.320 mmol) was added to 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.034 g, 0.080 mmol, see Example 9), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.080 mmol) and TBTU (0.0308 g, 0.0961 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. It was stirred for 20 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.036 g, 79%). MS APCI (+) m/z 491.3 detected.
Reaction SMILES: O.NN.[OH-].[K+].O=[C:7]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)CO.O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCCc1cccs1
Temperature: 180 °C
Yield: 84.7 %

Procedure:
Hydrazine hydrate (99%) (2.2 MI, 45.9 mmol) and KOH pellets (2.37 g, 42.4 mmol) were added to a solution of 4-oxo-4-(thiophen-2-yl)butanoic acid (2.3 g, 12.48 mmol) in ethylene glycol (30 MI), and the reaction mixture was heated to 180° C. for 10 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was washed with diethyl ether, acidified with 6N HCl and then extracted with diethyl ether. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 2% MeOH in CH2Cl2), to get 4-(thiophen-2-yl)butanoic acid (1.8 g, yield 85%). 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.31-7.29 (m, 1H), 6.94-6.91 (m, 1H), 6.84-6.82 (m, 1H), 2.82-2.77 (t, J=7.7 Hz, 2H), 2.27-2.22 (t, J=7.3 Hz, 2H), 1.86-1.76 (m, 2H). MS (ESI) m/z: Calculated for C8H10O2S: 170.04. found: 170.8 (M+H)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C([Mg]Cl)(C)C.[B:22](OC)([O:25]C)[O:23]C.C(OB1OC(C)(C)C(C)(C)O1)(C)C>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:22]([OH:25])[OH:23])=[CH:3][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)c1cc(I)ccc1C1OCCO1
Reactant: COB(OC)OC
Agent: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (Example I-IX-7) according to the procedure described for Example V-18, with the following exceptions: the aryl iodide and i-PrMgCl were aged 45 min before introduction of the electrophile (instead of 30 min); trimethyl borate was used as the electrophile (instead of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane); the dried organic extracts were concentrated to dryness and triturated with Et2O/hexanes (instead of flash chromatography). White solid. LC/MS (method A) 2.22 min, m/z 417 ({2[M−glycol]−H2O}−H, 23%), 217 ([M−glycol]−H, 57%), 189 (100%, −ve ion).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of methyl 5-(N-t-butoxycarbonyl-N-methylamino)valerate (557 mg) in methanol (6 ml) and 1 N sodium hydroxide solution (3.41 ml) was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo, and the residue was poured into water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (20 ml×3). The extract was collected and washed with water (40 ml×2) and brine (40 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 5-(N-t-butoxycarbonyl-N-methylamino)valeric acid (470 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([OH:36])[CH:29]=[CH:28]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([O:36][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)[CH:29]=[CH:28]2
Reactant: Oc1ccc2cc(Br)ccc2c1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc4cc(Br)ccc4c3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline (prepared as described in WO 03/33472) (0.465 mg, 1.93 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Example 3a) (0.65 mg, 1.93 mmol) and DMAP (0.235 mg, 1.93 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes) to give the title compound as an orange foam. MS (ESI, pos. ion) m/z: 541.1 (M+1). Mass Calc'd for C27H26BrFN2O4: 540.11.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]1[OH:8])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]1[O:8][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1(CC)CCCC1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCCC1OC(C)=O

Procedure:
5.58 grams of ethyl 1-ethyl-2-hydroxy-cyclopentane carboxylate obtained in Example 15 was diluted with 50 ml of methylene chloride. To the solution were added several drops of concentrated sulfuric acid, then dropwise added 4.32 ml of acetic anhydride. The mixture was allowed to react under reflux condition for 2 hours. The reaction mixture was washed with 50 ml of ethyl acetate and 50 ml of water, and organic layer was separated. Then the organic layer was washed with 10% aqueous solution of sodium carbonate twice, then with saline solution to neutrality, and dried over anhydrous magnesium sulfate. Removing solvent gave 5.91 g of colorless liquid. Yield after chromatography purification: 83.20%. MS: m/e 228(M+′), 183(M+—OCH2CH3), 169 (M+—CH3CO2), 158, 155, 140, 129, 113, 101.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[C:7]2[CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:6]2=[N:5]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[C:6]2=[N:5][N:4]([CH2:3][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:8]=[C:7]2[CH2:9][CH2:10]1
Reactant: CC1(C)CCc2cn(CCl)nc21
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCc2cn(CC(C#N)(C#N)CCC(F)(F)F)nc21
Yield: 33.2 %

Procedure:
0.58 g of 2-(chloromethyl)-6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole hydrochloride and 0.43 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 0.73 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of [(6,6-dimethyl-5,6-dihydro-cyclopenta[c]pyrazole-2(4H)-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (5), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:13]1=[O:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cccc2c1CCC2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cccc2c1CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 44.8 %

Procedure:
A mixture of 0.5 g 4-methyl-1-indanone, 1.37 g oxindole and 3 ml piperidine in 5 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate and concentrated. The resulting solid was precipitated from ethyl acetate/hexanes (2×) followed by methylene chloride/hexanes to afford 400 mg of 3-(4-methyl-indan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([OH:14])=O)=[C:9]([CH3:11])[N:10]=1)=[O:4].COC(NC1SC(C(Cl)=O)=C(C)N=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:36][CH:37]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:38]#[N:39]>C(N(CC)CC)C>[C:38]([CH:37]([NH:36][C:12]([C:8]1[S:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:10][C:9]=1[CH3:11])=[O:14])[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)#[N:39]
Reactant: N#CC(N)c1cccs1
Reactant: COC(=O)Nc1nc(C)c(C(=O)O)s1
Agent: COC(=O)Nc1nc(C)c(C(=O)Cl)s1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 32.1 %

Procedure:
1.7g of 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.8g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.5g of amino-thiophen-2-yl-acetonitrile hydrochloride and 2.4ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.85g (Yield 32%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:39]1([NH:45][CH2:46][CH2:47][OH:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[OH:48][CH2:47][CH2:46][N:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][CH:9]=2)[N:15]=1
Reactant: OCCNc1ccccc1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(OS(=O)(=O)C(F)(F)F)n3)CN(C(=O)OC(C)(C)C)CC4)cc2)cn1
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CN(C(=O)OC(C)(C)C)CC4)cc2)cn1
Temperature: 70 °C
Yield: 90.5 %

Procedure:
tert-Butyl 2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1 g, 1.80 mmol) and 2-(phenylamino)ethanol (0.228 mL, 1.80 mmol) in dimethylsulfoxide (3 mL) were charged in a thick wall glass, which was sealed and heated under microwave irradiation at 70° C. for 7 h. The solvent was evaporated together with toluene, the crude impregnated in silica gel and purified by flash chromatography (ISCO) using dichloromethane/methanol (0-10%) as eluent and the solvent evaporated under reduced pressure yielding tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.882 g, 90%). MS (ESI) (M+H) m/z 542
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[S:38][CH:39]=[CH:40][N:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:36][CH2:35][CH2:34][CH:33]5[C:37]5[S:38][CH:39]=[CH:40][N:41]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: c1csc(C2CCCN2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC5c5nccs5)c4)cc23)CC1
Yield: 30.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-pyrrolidinyl)-1,3-thiazole (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (20.0 mg, 30.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:15](=[O:26])[C:16]4[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=4[N:18]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[C:32]1([NH:38][C:15]([C:16]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=2[NH:18][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[O:14])=[O:26])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-methyl-4-oxo-4H-benzo[d][1,3]oxazine-6-carbonitrile (1.2 g, 2,8 mmol) (prepared according to WO 04/067528) in tetrahydrofuran (40 ml), is added bicyclopropyl-1-ylamine hydrochloride (0.6 g, 4.2 mmol) and 1.2 ml (8.4 mmol) triethylamine, and the solution is heated at a temperature of 60° C. for 8 h. The solution is cooled down to ambient temperature and the solvent is evaporated. Then the mixture is triturated in 100 ml water and the crystals are washed with water and ether to afford 0.85 g of the title compound. The mother liquor is evaporated and a second crop of crystals is obtained by crystallisation in diisopropylether to afford 0.46 g of the title compound (F: 270-272° C.).
Reaction SMILES: [CH3:1][OH:2].CC(C)(C)CCN[C:8]([C:10]1[C:19]2[CH2:18][CH2:17][CH:16](CCN3CCC(C4C=CC=CC=4)CC3)[C:15](=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:8]([C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)CCNC(=O)c1cccc2c1CCC(CCN1CCC(c3ccccc3)CC1)C2=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CCCC2=O
Temperature: 80 °C
Yield: 90 %

Procedure:
A 450-mL Parr bomb was charged with methanol (81 mL), DMF (160 mL), compound 2 (24.0 g, 81.6 mmol), palladium acetate (549 mg, 2.45 mmol), 1,3-bis(diphenylphosphino)-propane (1.01 g, 2.45 mmol), and triethylamine (23 mL, 163 mmol). The bomb was purged with carbon monoxide using 2 fill/vent cycles. The bomb was repressurized to 150 psi and was heated to 80° C. for 3 hours. During this time additional CO was admitted to maintain the pressure at 150 psi. The bomb was cooled to room temperature and vented. A second identical run was made. The combined reactions were diluted with methylene chloride (2 L), washed with water (4×800 mL), dried (MgSO4) and concentrated in vacuo to a black solid. Chromatography (flash, silica, 120 mm dia×20 cm, 2% ethyl acetate/methylene chloride) provided semi-pure product. Recrystallization of this material from hot hexanes in 2 crops followed by chromatography of the final mothor liquors (silica gel, methylene chloride (700 mL) then 2% ethyl acetate/methylene chloride) provided a total of 30.3 g (90%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Pd+2].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Temperature: 85 °C
Reaction time: 15 h

Procedure:
A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6-bromothiochroman (Compound 66) 314 mg (3.2 mmol) of trimethylsilyl acetylene, 40 mg (0.21 mmol) of cuprous iodide, 80 mg (0.11 mmol) of bis (triphenylphosphin) palladium (II) chloride and 1 ml of triethylamine was degassed under nitrogen and heated in a sealed tube at 85 degrees C. for 15 h. The mixture was then treated with a further 20 mg (0.11 mmol) of cuprous iodide and 40 mg (0.06 mmol) of the palladium (II) catalyst. The mixture was then heated under a nitrogen atmosphere in the sealed tube at 100 degrees C. for a further 64 h. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 0.28 (9H, s), 1.30 (6H, s), 1.88-1.97 (2H, m), 2.33 (3H, s), 2.97-3.05 (2H, m), 6.92 (1H, s), 7.43 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)#[N:2].[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([CH:24]=[CH:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(C=Cc2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixed liquid of 100 mg of 3-(2-cyanophenyl)-1-phenyl-5-bromo-1,2-dihydropyridin-2-one, 100 mg of 2-vinylpyridine, 6 mg of palladium acetate, 17 mg of tri-(o-tolyl)phosphine and 3 ml of triethylamine was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 16 mg of the title compound as a white powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.CN([CH:21]=[O:22])C.O>C1COCC1>[CH:14]1([S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:21]=[O:22])[CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccccc1SC1CCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1SC1CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of n-butyllithium (7.35 mL of a 1.6 M solution in hexanes, 11.7 mmol) in dry THF (15 mL) at −78° C. was added dropwise over 10 minutes a solution of (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol) in dry THF (15 mL) and the resulting solution stirred at −78° C. for 30 minutes. Anhydrous DMF (1.14 mL, 14.7 mmol) was then added, and the solution stirred at −78° C. for 5 minutes, before allowing to warm to room temperature and stirring for a further 1 hour. Water was then added, and the volatiles removed in vacuo, before extracting the mixture with ethyl acetate (×3). The combined organics were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using flash column chromatography on silica gel (eluting with a gradient of 0 to 5% ethyl acetate) to afford 2-(cyclobutylthio)benzaldehyde (450 mg, 2.34 mmol, 48%).