Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:13]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:31][CH2:32]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(C)c4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(C)c4)cnc32)cc1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methyl-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (172 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (24 mg, 0.416 mmol), DIPEA (54 mg, 0.416 mmol) and ethanol (4 mL) to get 183 mg (97.3% yield) of the titled compound. MS: m/z=679.3 (M+1).
Reaction SMILES: C(O[K])(C)(C)C.[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CC1C=CC(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=1>COCCOC.CCO>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:30]#[N:31])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tBuOK (2.29 g, 20.45 mmol, 2.5 eq) was added in portions at −5° C. to a solution of 1-(pyridin-4-yl)piperidin-4-one (1.44 g, 8.18 mmol, 1 eq) and TOSMIC (1.91 g, 9.81 mmol, 1.2 eq) in DME (20 ml) and EtOH (0.5 ml), and then stirring was carried out for 2 h at RT. The reaction mixture was hydrolyzed with ice-water (50 ml), extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 4% MeOH in dichloromethane), the desired product was obtained in the form of a brown solid. Yield: 34% (530 mg, 2.83 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1.C(N(CC)CC)C.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([CH3:40])[CH3:37])[CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1
Reactant: CC(C)=O
Reactant: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(F)c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a stirred solution of 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one (120 mg, 0.28 mmol) and triethylamine (3.9 μL, 0.028 mmol) in 5.00 mL dichloromethane was added acetone (4.1 μL, 0.56 mmol) followed with sodium triacetoxyborohydride (124 mg, 0.56 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight, quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3×30.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (2% methanol in ethyl acetate/hexane) to give 7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (85 mg, 69%) as a white solid, which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 157-160° C.; 1H NMR (300 MHz, CD3OD) δ 7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H), 3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m, 2H), 1.76-1.52 (m, 2H), 1.34 (d, 6H); 13C NMR (75 MHz, CD3OD) δ 179.7, 157.6, 150.6, 150.4, 147.1, 143.9, 136.6, 125.8, 121.2, 120.3, 118.0, 103.9, 103.0, 94.3, 81.8, 60.1, 59.7, 47.6, 35.33, 35.30, 28.6, 28.5, 16.98, 16.96; MS (ES+) m/z 439.27 (M+1).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:50](Cl)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:48][CH2:47]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC(C)C)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-isobutylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and pivaloylchloride. MS: 525 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.29 min.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH3:18])=[CH:12][CH:11]=1>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C@H:17]([CH3:18])[C@H:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: C/C=C/c1ccc(Cl)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CCOC(=O)[C@@H]1[C@@H](C)[C@@H]1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 5.9 %

Procedure:
Ethyl diazoacetate (1.61 g, 12 mmol) was added over 90 minutes to a mixture of rhodium acetate (44 mg) in E-1-(4-chlorophenyl)-1-propene (2.243 g, 12 mmol) at 90° C. with stirring. Heating was continued for 60 minutes. On cooling the mixture was chromatographed with EtoAc/hexane to yield 170 mg of racemic ethyl (1R,2S,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanecarboxylate. (Another isomer was also isolated.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1ccc(Br)nc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1

Procedure:
Prepared from 2,5-dibromopyridine and 1-t-butyloxycarbonylpiperidin-4-ol by the method of Example 10 (b).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Cc1cnc(N)c(Br)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Temperature: 100 °C

Procedure:
3-Bromo-5-methylpyridin-2-amine (0.5 g, 2.7 mmol), 3,4-difluorophenylboronic acid (0.5 g, 3.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.1 g, 0.1 mmol) were dissolved in a mixture of dioxane (10 mL) and 1M aqueous sodium carbonate solution (8 mL) under argon and the mixture was heated to 100° C. for 1 hour. The reaction was diluted with ethyl acetate, separated and the organic layer was washed with brine, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:1) as eluent. The title compound was obtained as a light brown crystalline solid (0.6 g, quant.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]1[CH2:28][N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([O:41][CH3:42])[C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:40][C:38]2[C:37]([O:41][CH3:42])=[CH:36][C:33]3[CH2:34][CH2:35][N:29]([CH2:28][CH:23]4[CH2:24][O:25][CH2:26][CH2:27][O:22]4)[CH2:30][CH2:31][C:32]=3[CH:39]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC1COCCO1)CC2

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was reacted with 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-[1,4]dioxan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide as a lyophylate (18%); 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.82 (d, J=7.94 Hz, 1H), 7.61 (m, 1H), 7.55 (s, 1H), 7.36 (m, 1H), 6.96 (s, 1H), 4.03 (m, 1H), 3.83 (s, 3H), 3.7-3.51 (bm H2O+6H), 3.27-3.03 (m, 9H), 2.75 (m, 1H), 2.65 (s, 6H); MS (m/e) 603.20 (M+H).
Reaction SMILES: [CH2:1](/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][CH:10]=[C:11]\1[NH:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.Cl>C(OCC)C>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:20])[CH3:21])[C:13]=1/[N:12]=[C:11]1/[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH2:8][CH2:9][CH2:10]/1)([CH3:24])[CH3:23]
Reactant: CCCC/N=C1\CCCC=C1Nc1c(C(C)C)cccc1C(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCNC1=CCCC/C1=N\c1c(C(C)C)cccc1C(C)C
Yield: 100.2 %

Procedure:
Charge a vial with N-((6E)-6-(butylimino)-1-cyclohexen-1-yl)-2,6-bis(1-methylethyl)-benzenamine (B) (3.0038 g, 9.1995 mmol, Example B) and toluene (30.0 mL). Stir the resulting yellow solution and add a solution of 1.0M HCl (aqueous, 0.46 mL, 0.46 mmol) in diethyl ether. Stir the resulting reaction mixture for 3 hours. To the mixture add hexanes (5 mL) and filter (syringe filter) to remove fine solids. Wash the filtered solids with hexanes (6 mL), and concentrate the filtrate overnight under reduced pressure to give 3.0107 g of the product (L)d as a thick brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 58.1 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (805 mg, 3.0 mmol) and 4-cyano-benzohydrazide (483 mg, 3.0 mmol) were coupled in a procedure analogous to that used for the preparation of inter mediate 3b. The crude product was purified by boiling in chloroform (10 mL) followed by cooling to 0° C. and filtration to yield product as a light yellow solid (718 mg, 50%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.85 (br s, 2H), 8.09 (AA′XX′, J=8.2 Hz, 2H), 7.92 (AA′XX′, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.27 (m, 1H), 4.16 (dd, J=5.0, 7.3 Hz, 1H), 2.88 (br s, 1H), 2.34 (s, 3H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[C:24]1([CH2:30][SH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:30]([S:31][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH2:9])[CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: SCc1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(SCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (3.00 g, 14.5 mmol) and DMF (72 mL) was added K2CO3 (5.31 g, 29.0 mmol) and phenyl-methanethiol (3.94 g, 31.7 mmol). The mixture was heated to 70° C. for 18 h and then cooled to 23° C. The reaction mixture was dissolved in EtOAc (200 mL), washed with saturated sodium bicarbonate solution (100 mL), washed with brine (3×100 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-45% EtOAc/hexanes) to yield the titled compound (2.39 g, 56%). MS (ESI/CI): mass calcd. for C13H11ClN2O2S, 294.0; m/z found, 295.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 7.96 (s, 1H), 7.56 (s, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.05 (s, 1H), 4.27 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Reaction time: 1.5 h

Procedure:
The reaction product of (a), 1 liter of epichlorohydrin and 20 gm of benzyltrimethylammonium chloride (BTMAC) dissolved in 12 ml of water are charged to a 2 liter 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, thermoregulator, condenser, Dean-Stark Trap and dropping funnel. The mixture is then heated to about 50° to 55° C. at high vacuum of 70 torr with stirring resulting in a vigorous reflux of the epichlorohydrin. 109 gm of NaOH (50% solution) is slowly added to the mixture over a period of 2 hours. The water/epichlorohydrin mixture is removed by distillation as soon as the azeotrope is formed. Upon completion of the addition, the epichlorohydrin is returned to the reaction mixture and the reaction is allowed to continue for an additional 1.5 hours. The reaction mixture is then cooled to room temperture and washed with 300 ml of ice water and separated. The organic layer is then washed with another 300 ml of water and the pH adjusted to about 5-6 using 10% aqueous acetic acid. The organic layer is then washed a third time with 300 ml of water and separated. The epichlorohydrin is then removed by distillation at reduced pressure (from 70 to 2 torr). The final distillation condition about less than 5 torr/110° C. The distillation is continued until no volatile could be distilled to ensure the complete removal of the epichlorohydrin. The yield is 330 gm. The epoxy value is 0.306 eq/100 g and the viscosity is 1310 cps at 25° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][C:14]([O:16]C)=[O:15])[S:9][C:8]2=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Li+].Cl>CN(C)C=O.O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][C:14]([OH:16])=[O:15])[S:9][C:8]2=[N:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Yield: 67.9 %

Procedure:
A mixture of methyl [3-cyclohexyl-2-(cyclohexylimino)-4-oxo-5-thiazolidinylidene]acetate (5.0 g, 14 mmoles) and anhydrous lithium iodide (7.6 g, 57 mmoles) in N,N-dimethylformamide (30 mls) is heated under argon to reflux. After six hours the mixture is cooled, diluted with water, acidified with 4N HCl, and extracted twice with dichloromethane. The combined extracts are washed with brine and dried over MgSO4. The solvent is removed to afford a syrupy residue which evenually crystallizes. Recrystallization from acetonitrile gave the product (3.2 g), mp 189°-190° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CC[C@@H](O)C1

Procedure:
By using (R)-3-hydroxypyrrolidine (2.0 g) as a starting material, the title compound (210 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37](I)[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>C(Cl)Cl.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N4 -(n-pentyloxycarbonyl)cytidine (130 mg, 0.18 mmol) in CH2Cl2 (2 ml) and Et3N(2 ml) Cul (10.7 mg, 0.1056 mmol), Pd(PPh3)2Cl2 (2.6 mg, 0.0036 mmol), and trimethylsilyl-acetylene (58.6 μl, 0.40 mmol) were added and stirred for 2 hours at room temperature under Ar in the dark. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc(25 ml×3), washed with 2% aq. EDTA.2Na(10 ml×2), water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (eluent: 10% EtOAc/n-hexane) to give 2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-[(trimethylsilyl)ethynyl]-N4 -(n-pentyloxycarbonyl)-cytidine as a colorless amorphous solid. (30.2 mg, 26% yield)
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH2:19]([O:24][CH:25]1[CH:27]([C:28](O)=[O:29])[C:26]1([CH3:32])[CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:19]([O:24][CH:25]1[CH:27]([C:28]([O:18][CH:3]([C:1]#[N:2])[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)=[O:29])[C:26]1([CH3:31])[CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CCCCCOC1C(C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCOC1C(C(=O)OC(C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg., 1.8 mmol), 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2 mmol). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueons sodium bocarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with ether/hexane to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.CN1CCOCC1.[C:18](OCC1C=CC=CC=1)(=[O:21])[C:19]#[CH:20]>C1COCC1>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]3[C:4]=2[O:10][CH2:20][CH2:19][C:18]3=[O:21])[O:9]1
Reactant: C#CC(=O)OCc1ccccc1
Reactant: Oc1cccc2c1OCO2
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CCOc2c1ccc1c2OCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-methylenedioxyphenol (27 g) and N-methyl morpholine (19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over a period of 30 minutes with cooling. After the addition was complete the reaction was stirred at room temperature for 1.5 hours followed by concentration. The residue was taken up into Et2O (500 ml), washed with 10% HCl (2×100 ml), dried over MgSO4. filtered and concentrated. This material was subjected to hydrogenation with 10%Pd/C in methanol at 4 atm. The reaction was filtered and concentrated. The resulting saturated acid was dissolved into methanesulfonic acid (350 ml) and stirred for 24 hours. The reaction was poured onto ice and extracted with CH2Cl2. The organic layer was washed with saturated Na2CO3, dried over MgSO4, filtered and concentrated to provide the desired material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1nnsc1C(=O)CBr
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2snnc2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole hydrobromide*.