Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:30])[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: CCc1c(C(=O)OC(C)C)c2cc(Cl)ccc2[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCc1c(C(=O)OC(C)C)c2cc(Cl)ccc2[nH]c1=S

Procedure:
150 mg (0.51 mmol) of isopropyl 6-chloro-3-ethylquinolin-2(1H)-one-4-carboxylate (Example 10) are reacted with Lawesson's reagent according to the process described in Example 5 (reaction time 5 hours at reflux temperature) and purified by means of chromatography on silica gel as indicated above (mobile phase: n-heptane/ethyl acetate=2/1).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[CH2:16]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:36]1[NH:40][N:39]=[CH:38][CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:36]1[CH:37]=[CH:38][N:39]([CH2:3][CH2:2][C:1]#[N:4])[N:40]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CC#N
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC#N)n4)n3Cc3ccccc3)n12
Reaction time: 0.05 h

Procedure:
2-Propenenitrile (3.0 μL, 0.046 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 μL, 0.015 mmol) were added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (5.0 mg, 0.015 mmol, from Example 62) in acetonitrile (0.20 mL). After 3 minutes at room temperature, the reaction was found to be complete and was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.9 mg, 67%).
Reaction SMILES: C([NH:5][C:6]1[C:11]([Cl:12])=[C:10]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=2[O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:15])[C:9]([Cl:36])=[CH:8][N:7]=1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[NH2:5][C:6]1[C:11]([Cl:12])=[C:10]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=2[O:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[O:15])[C:9]([Cl:36])=[CH:8][N:7]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cnc(NC(C)(C)C)c2Cl)c(OCCc2ccc(F)cc2)c1OC
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Cc2c(Cl)cnc(N)c2Cl)c(OCCc2ccc(F)cc2)c1OC

Procedure:
2-(2-tert-Butylamino-3,5-dichloro-pyridin-4-yl)-1-{2-[2-(4-fluoro-phenyl)-ethoxy]-3,4-dimethoxy-phenyl}-ethanone obtained from example 300 (16.5 mg, 0.0308 mmol), triethylsilane (2 eq.) and TFA (0.1 mL) in dichloroethane (0.2 mL) was heated to 50° C. for 24 hours. The crude mixture was evaporated in vacuo, redissolved in dichloroethane (1 mL) and washed with NaHCO3 (sat, 2×0.5 mL). The organic phase was dried over Na2SO4 and the solvent evaporated in vacuo. Pure 2-(2-amino-3,5-dichloro-pyridin-4-yl)-1-{2-[2-(4-fluoro-phenyl)-ethoxy]-3,4-dimethoxy-phenyl}-ethanone was obtained by flash chromatography using a gradient of MeOH in dichloromethane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[N:15]([CH2:16][CH2:17]O)[C:14]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[C:11]2=[N:12][C:13]3[C:14](=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][CH:22]=3)[N:15]2[CH2:16][CH2:17]1
Reactant: COC(=O)c1cccc2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 14 h
Yield: 88.8 %

Procedure:
To a solution of methyl 3-{[(2,4-dichloro-6-methylphenyl)carbamothioyl]amino}-2-[(2-hydroxyethyl)amino]benzoate (300 mg, 0.70 mmol) in tetrahydrofuran (7.0 mL) was added 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol) at room temperature. The mixture was stirred at 50° C. for 14 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (210 mg, 0.53 mmol, 76%) as a pale yellow solid. To a solution of methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (200 mg, 0.507 mmol) and triethylamine (0.28 mL, 3.8 mmol) was added methanesulfonyl chloride (0.079 mL, 1.02 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr and at room temperature for 14 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 8 hr. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.45 mmol, 89%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH2:13][C:12]2=[O:20])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4]>C(OC(=O)C)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:18][O:19][C:16](=[O:17])[CH3:15])([CH2:16][O:17][C:3](=[O:2])[CH3:5])[CH2:14][CH2:13][C:12]2=[O:20])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(N2C(=O)CCC2(COC(C)=O)COC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 197.2 %

Procedure:
A suspension of 1-[4-methoxycarbonyl-2-(nitro)phenyl]-5,5-bis(hydroxymethyl)-pyrrolidin-2-one (500 mg, 1.54 mmol) from example 6 in acetic anhydride (0.5 mL) was treated with DMAP (15 mg) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was dried under high vacuum and the resulting crude oil was purified by flash chromatography (silica gel; 10% ethanol in ether) to give 620 mg (98.5%) of 1-[4-methoxycarbonyl-2-(nitro)phenyl]-5,5-bis(acetyloxymethyl)pyrrolidin-2-one as an oil which solidified upon standing, mp, 61-63° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH2:16]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)N1CCC(O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a solution of ethyl bromo(phenyl)acetate (5.0 g) in ethanol (20 mL) was added 4-piperidinol (5.05 g) and the mixture was stirred at 60° C. for 4 hours. The mixture was poured into dilute sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethylacetate (3:7) to afford ethyl (4-hydroxypiperidin-1-yl)(phenyl)acetate (5.21 g) as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=[O:12])[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[O:12]=[C:9]1[C:8](=[O:13])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH:10]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(c2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=O
Temperature: 25 °C

Procedure:
A solution of the product of Example 61 in THF is added to a solution of lithium di-iso-propylamide (LDA) in THF at -78° C. After 2 h at -78° C. a solution of ethyl bromoacetate is added and the reaction is allowed to warm to room temperature. After an aqueous workup the crude product is chromatographed on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][C:39]#[C:40][CH:41]2[CH2:43][CH2:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][C:39]#[C:40][CH:41]2[CH2:43][CH2:42]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reactant: OC[C@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: OC[C@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(OCC#CC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Compound AW was prepared by reaction of (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D2) with 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate (intermediate AU) in the presence of Cs2CO3 using the same procedure as described above for compound AV. 1H NMR (CD3OD): δ 7.34˜7.30 (3H, m), 7.11˜7.08 (2H, d, J=8.8 Hz), 6.86˜6.84 (2H, d, J=8.8 Hz), 4.61 (2H, d, J=1.6 Hz), 4.58 (1H, d, J=4 Hz), 4.19˜4.17 (1H, m), 4.03˜4.00 (4H, m), 3.94˜3.93 (1H, q), 3.84˜3.80 (1H, m), 3.68˜3.64 (1H, q), 1.29˜1.24 (1H, m), 0.78˜0.75 (2H, m), 0.62˜0.59 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)N6CCOCC6)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.86 mmol) and morpholine (0.15 ml, 1.7 mmol). The solution was stirred at room temperature for two hours then was concentrated in vacuo. The brown residue was purified via MPLC chromatography (eluted with 0-5% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=503.0 [M+1]+. Calc'd for C25H22N6O4S: 502.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][C:43]1=[O:48]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:45]4[CH2:46][CH2:47][NH:42][C:43](=[O:48])[CH2:44]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:41])[NH:37][S:38]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CCN1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess piperazin-2-one (200 mg, 2 mmol) to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazin-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CN(C=O)C>[C:8]([C:7]1[C:2]([NH:16][C@@H:15]([CH3:17])[C:14]([O:13][CH2:11][CH3:12])=[O:18])=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: CCOC(=O)[C@H](C)N
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)Nc1ncccc1C#N
Yield: 22.8 %

Procedure:
A solution of 2-chloro-3-cyanopyridine (2 g, 14.4 mmol), L-alanine ethyl ester hydrochloride (3.3 g, 21.6 mmol), sodium carbonate (5.9 g, 43 mmol) in pyridine (1.75 mL) and DMF (20 mL) was heated to 125° C. for 36 h. The reaction was quenched with water and extracted with ethyl acetate (3×15 mL). The product was purified using column chromatography (10% MeOH in CH2Cl2) to yield a pale yellow solid (720 mg, 23%): 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 7.69-7.67 (m, 1H), 6.67-6.64 (m, 1H), 4.77-4.74 (m, 1H), 4.23-4.19 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.30-1.26 (m, 3H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[Si]([O:36][C@@H:37]1[C@H:41]([O:42][Si](C(C)(C)C)(C)C)[C@@H:40]([CH3:50])[O:39][C@H:38]1[N:51]1[CH:58]=[C:57]([F:59])[C:55]([NH2:56])=[N:54][C:52]1=[O:53])(C(C)(C)C)(C)C>C(#N)C.CN(C)C1C=CN=CC=1>[F:59][C:57]1[C:55]([NH:56][C:1](=[O:12])[C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[N:54][C:52](=[O:53])[N:51]([CH:58]=1)[C@@H:38]1[O:39][C@H:40]([CH3:50])[C@@H:41]([OH:42])[C@H:37]1[OH:36]
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)c3ccc4c(c3)OCO4)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
A solution of piperonylic acid (0.42 g) in dry acetonitrile (5 ml) containing triethylamine (0.36 ml) was treated with diethyl chlorophosphate (0.37 ml) for 1 hour. To the reaction mixture were added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (1.0 g) obtained in Reference example (a), triethylamine (0.36 ml) and 4-dimethylaminopyridine (0.05 g). After stirring of the mixture for 12 hours at room temperature, acetonitrile was evaporated under reduced pressure. The residue was partitioned between water and ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained powder was dissolved in tetrahydrofuran (6.3 ml) containing tetrabutylammonium fluoride (1.65 g) and the reaction mixture was stirred for 1 hour. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (isopropanol-dichloromethane) followed by recrystallization from ethyl acetate to give 0.5 g of 5'-deoxy-5-fluoro-N4 -piperonyloylcytidine, mp 124°~125° C.: MS 394 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:27])[CH:11]([CH2:16][C:17]3[N:22]=[C:21]([NH:23][CH3:24])[C:20]([C:25]#[N:26])=[CH:19][CH:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:28])[CH:3]=1.[F-].[Cs+].[CH2:31]([Sn](CCCC)(CCCC)C#CC)[CH2:32][CH2:33]C.CN(C)C=O>O.C(OCC)C.[Cu]I.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:8][C:6]1[CH:7]=[C:2]([C:31]#[C:32][CH3:33])[CH:3]=[C:4]([CH3:28])[C:5]=1[C:9]1[C:10](=[O:27])[CH:11]([CH2:16][C:17]2[N:22]=[C:21]([NH:23][CH3:24])[C:20]([C:25]#[N:26])=[CH:19][CH:18]=2)[CH2:12][C:13]=1[O:14][CH3:15]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CNc1nc(CC2CC(OC)=C(c3c(C)cc(Br)cc3C)C2=O)ccc1C#N
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC#Cc1cc(C)c(C2=C(OC)CC(Cc3ccc(C#N)c(NC)n3)C2=O)c(C)c1
Temperature: 120 °C
Yield: 23.6 %

Procedure:
A microwave vial was charged with 6-[[3-(4-bromo-2,6-dimethyl-phenyl)-4-methoxy-2-oxo-cyclopent-3-en-1-yl]methyl]-2-(methylamino)pyridine-3-carbonitrile (150 mg, 0.34 mmol), caesium fluoride (CsF, 104 mg, 0.68 mmol), copper(I) iodide (CuI, 13 mg, 0.068 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (37 mg, 0.05 mmol), tributyl(prop-1-ynyl)stannane (125 mg, 0.41 mmol) and N,N-dimethylformamide (1.5 ml), sealed and heated at 120°C. under microwave irradiation for 60 minutes. Further caesium fluoride (52 mg, 0.34 mmol), copper(I) iodide (6.5 mg, 0.034 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (18.5 mg, 0.025 mmol) and tributyl(prop-1-ynyl)stannane (63 mg, 0.21 mmol) were added and the reaction heated at 120 C under microwave irradiation for a further 30 minutes. The reaction was allowed to cool to room temperature, diluted with water (10 ml) and diethyl ether (10 ml) and filtered through Celite. The filtrate phases were separated and the aqueous phase extracted with further diethyl ether (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was dissolved in EtOAc, absorbed onto silica and purified by flash chromatography on silica using an EtOAc/isohexane gradient to give the desired product (32 mg, 24%) as a yellow gum. 1H NMR (400 MHz, CDCl3) 7.45 (d, 1H), 7.05 (2×s, 2×1H), 6.45 (d, 1H), 5.20 (br, 1H), 3.50 (s, 3H), 3.50-3.40 (m, 1H), 3.20-3.15 (m, 1H), 3.05 (d, 3H), 2.80-2.05 (m, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:54]=[CH:53][C:39]([CH2:40][CH:41]([CH:51]=O)[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:38][CH:37]=1)#[N:35].[Cl-].[NH4+]>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:54]=[CH:53][C:39]([CH2:40][CH:41](/[CH:51]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:38][CH:37]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCC(C=O)Cc1ccc(C#N)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.5 %

Procedure:
15.98 ml (39.95 mmol) of a 2.5 M solution of n-butyllithium in hexane are slowly added to a solution of 6.411 g (14.27 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 300 ml of anhydrous THF at 0° C. Then, at this temperature, 4.1 g (14.27 mmol) of ethyl 6-(4-cyanobenzyl)-7-oxoheptanoate from Example 111A are slowly metered in. After warming to room temperature, the reaction solution is stirred for 12 hours and then mixed with saturated ammonium chloride solution and concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 1.75 g (4.64 mmol, 32% yield) of a colorless solid are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCCCc1ccc(OCc2ccccc2)cc1
Yield: 71 %

Procedure:
A suspension comprising 3.0 g of 8-(4-hydroxyphenyl)octanol, 3.0 g of anhydrous potassium carbonate, 50 ml of dry acetone and 1.9 ml of benzyl bromide was heated under reflux for 16 hours. After the completion of the reaction, the potassium carbonate was filtered off and the filtrate was concentrated on an evaporator. The white solid thus obtained was precipitated from chloroform-hexane (1:4). As a result, 3.0 g of the desired compound was obtained (yield: 71%).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1COCCN1
Product: O=Cc1c(N2CCOCC2)n(-c2ccccc2)c2ccccc12

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with morpholine as described in Step 2 of Example 29 to afford 2-(morpholin-4-yl)-1-phenyl-1H-indole-3-carboxaldehyde (885 yield) as a fluffy, creamy solid. ESI/MS 307 (M+H); RT 2.99 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=6 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.45 (4H, m); 3.28 (4H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([CH3:34])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH3:31])[C:21]=2[CH2:32][OH:33])[CH:15]=[CH:16][C:17]=1[CH3:18].CCN(CC)CC>C(Cl)Cl>[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([CH3:34])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH3:31])[C:21]=2[CH:32]=[O:33])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N(C)c2c(CO)n(C)c(=O)c3ccccc23)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(N(C)c2c(C=O)n(C)c(=O)c3ccccc23)cc1C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of oxalyl chloride (0.015 mL, 0.172 mmol) in DCM (5 mL) at −70° C. was added dropwise DMSO (0.024 mL, 0.344 mmol). After 15 min a solution of 4-[(3,4-dimethylphenyl)(methyl)amino]-3-(hydroxymethyl)-2-methyl-1(2H)-isoquinolinone (25 mg, 0.078 mmol) in DCM (1 mL) was added slowly, and the mixture was kept at −78° C. for 30 min. Then NEt3 (38 uL) was added and the reaction was kept at −78° C. for 1 hour. The mixture was quenched with aq. NaHCO3 and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give the crude title compound as yellow oil (16.9 mg, 61.4%). 1H NMR (400 MHz, CDCl3) δ ppm 9.97-9.78 (m, 1 H), 8.64-8.46 (m, 1 H), 7.75-7.54 (m, 2 H), 7.51-7.42 (m, 1 H), 7.07-6.92 (m, 1 H), 6.59-6.38 (m, 2 H), 3.87 (s, 3 H), 3.40 (s, 3 H), 2.18 (d, J=6.3 Hz, 6 H); ES-LCMS: 321.1 (M+1).