Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][O:23]C(Cl)Cl.Cl>ClCCl>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[CH:22]=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(Cl)Cl
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1c(Cc2ccccc2)sc2ccccc12
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Tin chloride (14.0 mL, 119.6 mmol) was added dropwise into a cold (−20° C.) solution of 2-benzyl-benzo[b]thiophene (13.4 g, 59.8 mmol) in dichloromethane (150.0 mL). After 1 h, to the reaction was added dropwise dichloromethyl methyl ether (119.6 mmol). The mixture was allowed to gradually come to 0° C., and then stirred for 20 hours. The mixture was carefully poured into HCl (2 N) and ice, and extracted with ethyl ether. The ethereal extracts were dried (MgSO4) and concentrated to give 12.9 g (85%) of the title compound after crystallization from ethyl ether/hexanes, yellow solid mp 86-88° C.; mass spectrum m/z 252 (M+). Anal. Calcd. for C16H12O5: C 76.16; H, 4.79. Found: C, 75.77; H, 4.85
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][P:16]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)/C(=N\OC)c1csc(N)n1
Solvent: c1ccncc1
Product: CCOC(=O)/C(=N\OC)c1csc(NP(=O)(OCC)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of 4.6 g (0.02 mol) of ethyl 2-(aminothiazol-4-yl)-Z-2-methoxyiminoacetate in 40 ml pyridine at 10°-20° was added 9.0 ml (0.6 mol) diethyl chlorophosphate. The solution was stirred at room temperature for 2 hours. Pyridine was evaporated and the residue was codistilled with benzene and partitioned between water and methylene chloride. The methylene chloride layer was washed with excess 10% aqueous HCl, water, aqueous bicarbonate, saturated sodium chloride, and dried over sodium sulfate. Upon evaporation, 5.5 g brown oil was obtained which was purified on Biosil A using hexane/ethyl acetate (1:4) to afford 2.8 g of yellow crystals, m.p. 96.5-98.0; NMR (300MH2, DCCl3) δ 1.35 (3t, 9, CH3), 3.97 (S, 3, OCH3), 4.17 (q, 4, OCH2), 4.39 (q, 2, OCH2), 6.93 (s, 1, thiazole H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccc3[nH]cc(C#N)c3c2)CCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1c1ccc2[nH]cc(C#N)c2c1

Procedure:
A solution of 2-(3-cyano-1H-indol-5-yl)-cyclopent-1-enecarboxylic acid ethyl ester (0.97 g, 3.46 mMol) in methanol (50 mL) was treated with 10% palladium(0) on carbon (0.35 g) and hydrogenated at 50 psi in a Parr apparatus for 22 h. The mixture was filtered through Celite® 545 and concentrated in vacuo to give the product as a clear oil which solidified upon standing (0.95 g, 97%). 1H-NMR (500 MHz, CDCl3) δ 8.76 (1H, br s), 7.65 (1H, d, J=2.0 Hz), 7.60 (1H, s), 7.25 (1H, d, J=8.5 Hz), 7.18 (1H, m), 3.71 (2H, m), 3.57 (1H, m), 3.21 (1H, m), 2.16 (m, 4H), 2.02 (1H, m), 1.78 (1H, m), 0.85 (3H, t, J=7.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH2:24]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=2)[C:19]([C:20]#[N:21])=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1)[CH3:25]
Reactant: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Reactant: C1COCCN1
Solvent: CC#N
Product: CCn1c(-c2ccc(OCCN3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 85 °C
Yield: 96.2 %

Procedure:
2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, is combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This is heated at 85° C. for 2 h. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yields 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[CH3:34]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][C:26]=1[CH3:34]
Reactant: Cc1nn(C)cc1C(=O)Nc1cnc(OCC(F)(F)F)c(Br)c1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3cn(C)nc3C)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 39, using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 58 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 96.1%, 439.1154 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:51]([NH:53][CH2:54][C:55]([C:57]1[C:58]([O:67][CH3:68])=[N:59][C:60]2[C:65]([CH:66]=1)=[CH:64][CH:63]=[CH:62][CH:61]=2)=O)=[O:52])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:51]1[O:52][C:55]([C:57]2[C:58]([O:67][CH3:68])=[N:59][C:60]3[C:65]([CH:66]=2)=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:54][N:53]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1nc2ccccc2cc1C(=O)CNC(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
PPh3 (2.0 eq.) and C2Cl6 (2.0 eq.) were dissolved in DCM (0.72 M) at room temperature and Et3N (4.0 eq.) was added, followed after 5 min of stirring by dropwise addition of a solution of F3 in DCM (0.36 M). The mixture was stirred at room temperature for 1 h and then was diluted with DCM, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude was purified by column chromatography (eluent: Petroleum ether/EtOAc from 94:6 to 2:3) to give the title compound as orange oil. MS (ES+) C32H37N3O6: 560 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[N:37]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[N:25][N:24]=[C:6]1/[CH:7]=[CH:8]/[C:3]1[O:10][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:11][N:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=Nc2ccccc2Cl)NN)cc1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cc4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (180 mg, 0.68 mmol) in 20 mL of PhMe was added 0.2 mL of POCl3. The mixture was stirred at reflux for 2 hours. After removal of solvent, the residue was dissolved in 20 mL of THF and 220 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-4-methylsulfonyl-benzamidine 5 added. The mixture was stirred at ambient temperature for 18 hours. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(5-((E)-2-(4-(2-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a solid. Yield: 30 mg, 8.3%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)O1>>[NH2:16][C:4]1[S:3][C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]3)[CH:33]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CCNCC4)c3)sc2N)cn1
Yield: 19 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate gave 274 as a pale brown solid (18 mg, 19% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.82 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.45 (s, 3H), 7.28 (dd, J=8, 7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.96 (dd, J=8, 2.5 Hz, 1H), 3.82 (s, 3H), 3.14 (t, J=5 Hz, 4H), 2.86 (t, J=5 Hz, 4H). Alkyl NH not seen. LCMS (ES+) m/z 384 (M+1)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:27]C(=O)OC(C)(C)C)([CH2:7][C:8]#[C:9][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:11]=2)[C:3]1=[O:35].S(=O)(=O)(O)O>O1CCOCC1.C(#N)C>[NH2:27][C@@:4]1([CH2:7][C:8]#[C:9][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:11]=2)[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 7) (99.5 g, 203.68 mmol) in 1,4-dioxane (750 mL) cooled with an ice/water bath to an internal temperature of 15° C. was added conc. sulphuric acid (75 mL, 1407 mmol) dropwise maintaining internal temperature below 20° C. over approximately 35 minutes. After complete addition, the reaction mixture was stirred at room temperature over 30 minutes. The reaction was poured into a beaker and washed in with ethyl acetate (400 mL) and a little water. The mixture was cooled to 15° C. and a solution of sodium carbonate (160 g in 1200 mL water) was added over 5 minutes. The mixture was filtered over a pad of celite and the remaining solids washed with ethyl acetate (400 mL). The filtrate phases were separated and the aqueous phase was extracted with ethyl acetate (2×400 mL). The combined organics were washed with brine (500 mL), dried over magnesium sulphate, filtered and evaporated to yield a foaming amber oil. This was twice dissolved in acetonitrile (100 mL) and evaporated and the resulting yellow foam dried under vacuum to give the title material (D8) in good purity by NMR, consistent spectroscopically with that produced by Method 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=O)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>O1CCOCC1>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[S:22])[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CCN1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: S=C1CCN(Cc2ccccc2)CCN1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-1,4-diazepan-5-one (2.00 g, 9.80 mmol) in anhydrous dioxane (40 mL), sodium bicarbonate (8.81 g, 105 mmol) and phosphorus pentasulfide (2.92 g, 13.1 mmol) were added. The mixture was heated to 75° C. for 6 h. Dioxane was removed under reduced pressure and the residue was treated with water (80 mL). The resultant mixture was stirred at 50° C. for 1 h and then stirred an additional 2 h at 25° C. Sodium chloride (30.0 g) was added to the mixture and the aqueous phase was extracted with dichloromethane. The organic phase was concentrated to yield the desired compound, which was used without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Temperature: 120 °C
Yield: 75.9 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (31 mg, 0.10 mmol) and glycine (78 mg, 1.04 mmol) in 0.5 M sodium methoxide/methanol (1.7 mL) was heated at 120° C. using a CEM microwave reactor for 30 min before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (18 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (1.2 mL). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.30 (br s, 1H), 9.42 (t, 1H), 8.96 (s, 1H), 8.14 (m, 2H), 7.67 (m, 3H), 4.02 (d, J=6.2 Hz, 2H); MS: (+) m/z 330.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[C:34]1[CH:33]=[C:32]([CH2:31][O:30][CH3:29])[CH:37]=[CH:36][CH:35]=1
Reactant: COCc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2cccc(COC)c2)c(OC)c1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a solution of Ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) (2 g, 5.8 mmol) in DME (36 mL) and water (9 mL) was added potassium carbonate (1.61 g, 11.6 mmol) and 3-(methoxymethyl)phenylboronic acid (962 mg, 5.8 mmol) and the mixture was degassed using argon stream for 30 minutes. Pd[PPh3]4 (330 mg, 0.29 mmol) was added and the mixture was heated at 80° C. under argon overnight. The solvents were removed under reduced pressure and the residue extracted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOH/hexanes) to yield 1.38 g (76%) of ethyl 2-(2-methoxy-5′-(methoxymethyl)biphenyl-4-yl)acetate. 1H NMR(400 MHz, dMSO): δ 1.16-1.20 (t, 3H), 3.27 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 4.06-4.11 (q, 2H) 4.41 (s, 2H) 6.89 (d, 1H), 7.00 (s, 1H) 7.19-7.24 (m, 2H), 7.34-7.36 (m, 3H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1CCNCC1
Product: [C-]#[N+]CC(=O)N1CCCCC1

Procedure:
To stirred and cooled (0° C.) methyl 2-isocyanoacetate (96% technical grade, 2.46 g, 24.63 mmol) was slowly added piperidine (3.22 mL, 37.85 mmol). The mixture was stirred for 1 h with continuous stirring at room temperature and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. 2-Isocyano-1-(piperidin-1-yl)ethanone, SLA 07116B, was obtained as an orange solid (3.13 g, 83% yield) that was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH2:15])=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>CO.C(Cl)Cl>[C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH:15][C:20]3[N:25]=[C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]4[NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:23]([Cl:38])=[CH:22][N:21]=3)=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1N)NC(=O)CN(C(C)=O)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(C(C)=O)C2
Yield: 10.6 %

Procedure:
In an analogous manner to procedure 1656g, 4-acetyl-8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.24 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (82 mg, 0.24 mmol) were coupled to provide N-{(1R,2R)-2-[2-(4-Acetyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (14 mg, 10%) as a pale yellow solid following preparative tlc (10% MeOH-DCM); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.63 (d, J=7 Hz, 1H), 5.46 (d, J=7 Hz, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.53 (s, 2H), 3.29 (m, 1H), 2.89 (s, 3H), 2.21 (m, 2H), 2.17 (s, 3H), 1.83 (m, 2H), 1.65 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 553 (M+1); mp 167° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl>[OH:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)OC)c1OC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl 2-methoxyisophthalate, prepared according to Example 4, (279 mg, 1.24 mmol) was dissolved in dry CH2Cl2 (5 ml), and the flask was flushed with argon. Boron trichloride (1M solution in heptane, 1.2 ml) was added, and the solution was stirred under argon for 1 hour at room temperature. After evaporation of the solvent, chromatography with 3:7 EtOAc:petroleum ether gave the product as a white solid. Yield: 237 mg (91%). 1H NMR (CDCl3) δ: 8.06 (d, 2 H, aryl), 6.94 (t, 1 H, aryl), 3.96 (s, 6 H, CO2CH3)
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH:18]=O)[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C>CN(C)C=O>[CH2:3]([N:10]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13](/[CH:18]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCc1c(C=O)cnn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/C(=O)OCC)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
Sodium hydride (60%, oily, 2.25 g) was added to a mixture of 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (12.60 g), ethyl diethylphosphonoacetate (10.69 g), and N,N-dimethylformamide (150 ml) at 0° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-(1-benzyl-5-propyl-1H-pyrazol-4-yl)propenoate (11.90 g, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: CCOC(=O)c1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1oc(N2CC[C@H](N)[C@H](OC)C2)nc1C
Yield: 100.8 %

Procedure:
The same operation as in Example (95b) was performed using ethyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-oxazole-5-carboxylate obtained in Example (107a) (0.32 g, 0.77 mmol), 10% Pd/C (0.3 g), ethyl acetate (3 mL) and methanol (3 mL), to obtain 0.22 g of the title compound as a brown oily substance (100%).
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]=[CH:4][I:5].N1C=CN=C1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[I:5][CH:4]=[CH:3][C:2]([CH3:11])([O:1][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(C)(O)C=CI
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCC(C)(C=CI)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1octene (Example 184) and 7.4 of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0° C under argon atmosphere. After stirring at 0° C for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65° C (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:32][CH3:33])[CH2:4][NH:5][CH:6]([C:10]1[N:11]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:12](=[O:20])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH:7]([CH3:9])[CH3:8].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:32][CH3:33])[CH2:4][N:5]([CH:6]([C:10]1[N:11]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:12](=[O:20])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH:7]([CH3:9])[CH3:8])[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(CNC(c1nc2cnccc2c(=O)n1Cc1cccc2ccccc12)C(C)C)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cnccc2c(=O)n1Cc1cccc2ccccc12)C(C)C)OC

Procedure:
A solution of 2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3-naphthalen-1-ylmethyl-3H-pyrido-[3,4-d]pyrimidin-4-one (522 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) is stirred at room temperature for 18 h. The reaction is washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water, and brine. The organic layer is dried (Na2SO4) and concentrated to yield the title compound, N-(2,2-dimethoxy-ethyl)-N-[2-methyl-1-(3-naphthalen-1-ylmethyl-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidin-2-yl)-propyl]-benzamide.