Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)cc(O)cc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(Br)c2c(c1)C(=O)NC2
Yield: 100 %

Procedure:
A mixture of Example 104B (103 mg, 0.45 mmol), Cs2CO3 (164 mg, 0.5 mmol) and t-butyl bromoacetate (0.075 mL, 0.5 mmol) in DMF (2.2 mL) was stirred overnight at room temperature, diluted with water, and filtered. The filter cake was dried to give 154 mg (45%) of the desired product. MS (ESI(+)) m/e 342,344 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([NH2:64])[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CO[CH:68]1[CH:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[N:86])=[CH:81][CH:80]=3)=[CH:75][CH:74]=2)[CH2:71][CH:70](OC)O1>ClCCCl>[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([N:64]1[CH:70]=[CH:71][C:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:80]=[CH:81][C:82]([C:85]#[N:86])=[CH:83][CH:84]=3)=[CH:75][CH:74]=2)=[CH:68]1)[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Agent: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Temperature: 87.5 °C
Yield: 39.1 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluroacetate salt, crude 3(R)-amino-N-(1(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(a); 0.876 mmol) was condensed with 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (326 mg, 1.05 mmol) in 1,2-dichloroethane (5 mL). The solution was heated at 85-90° C. for 5 hours, allowed to cool, and evaporated to give a brown oil which was purified via flash column chromatography with 1% HOAc/30% EtOAc/hex as eluant. HOAc was removed via azeotrope with n-heptane layers to provide 200 mg (39%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow powder, mp 149-50° C. 1H NMR (CDCl3): ∂ 7.74 (s, 4H), 7.59 (d, 4H, J=4.1 Hz), 7.32-7.18 (m, 10H), 7.05 (bm, 2H), 6.94 (t, 1H, J=2.2 Hz), 6.64 (t, 1H, 2.5 Hz), 6.58 (bm, 1H), 5.48 (d, 1H, J=7.8 Hz), 5.10 (d, 2H, J=3.1 Hz), 5.00 (dd, 1H, J=5.0, 9.3 Hz), 4.46-4.32 (m, 2H), 4.22-4.12 (m, 1H), 3.41 (dd, 1H, J=5.3, 17.1 Hz), 3.04 (dd, 1H, J=9.1, 17.1 Hz), 2.70-2.63 (m, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm−1. HRFABMS: Calculated for C37H33N3O4Cs (MH+Cs+): 716.1525. Found: 716.1503. Anal. Calculated for C37H33N3O4•0.4 CH2Cl2: C, 72.73; H, 5.52; N, 6.80. Found: C, 72.67, H, 5.53; N, 6.81.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:12])(=[O:11])=[S:10].[K+]>C(O)C.CCCCCC>[CH2:1]([O:12][S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[S:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
The title compound was prepared as described in General Method 2 using 0.05 mol of benzyl chloride, 0.05 moles of potassium thiotosylate in 150 mL of ethanol. The residue was dissolved in hexane and seeded with a crystal of the product to afford 10.8 g (77%) of benzyl-p-toluenethiosulfonate (m.p. 52-56.5° C.). 1H NMR (CDCl3) δ 2.45 (s, 3 H), 4.26 (s, 2 H), 7.18-7.30 (m, 7 H), 7.74 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c1C
Yield: 55 %

Procedure:
5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[C:10]1[S:15][CH3:16]
Reactant: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 4.63 g (17.66 mmol) N-(1,1-dimethylethyl)-1-methyl-2-(methylthio)-1H-pyrrole-3-sulfonamide in 50 mL of methylene chloride was added 50 mL of trifluoroacetic acid (TFA) under a nitrogen atmosphere. The orange reaction mixture was stirred at room temperature overnight ca. 16 hours. The reaction mixture was concentrated to a tan solid. Diethyl ether was added to the tan solid and was removed by evaporation to remove residual TFA. The solid was suspended in diethyl ether and filtered giving 2.9 g of the title compound as a solid, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Indoline-2-carboxylic acid methyl ester (32.7 g, 151.8 mmol) was dissolved in DCM (400 ml), and pyridine (37.4 ml, 459.0 mmol) was added thereto. A solution of 4-methoxybenzenesulfonyl chloride (31.6 g, 153 mmol) dissolved in DCM (100 ml) was then added, and stirring was carried out overnight at room temperature. The mixture was diluted with DCM and washed in succession with 0.5 M KHSO4, saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane/ethyl acetate 2:1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1c(F)cccc1F

Procedure:
To a suspension of 2,6-difluorobenzaldehyde (374.7 mg, 2.64 mmol), 1,1-dimethylnitroethane (541.6 mg, 5.25 mmol) and zinc (517.0 mg, 7.91 mmol) in ethanol (3.0 ml) was added acetic acid (940.5 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/2-2/1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([CH3:33])=[C:5]([CH3:34])[N:4]=2.[CH:35]([NH2:38])([CH3:37])[CH3:36]>>[CH:35]([NH:38][C:11]([C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:12])[N:4]=[C:5]([CH3:34])[C:6]([CH3:33])=[N:7]2)=[O:32])([CH3:37])[CH3:36]
Reactant: Cc1nc2cc3c(=O)oc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)nc3c(Cl)c2nc1C
Reactant: CC(C)N
Product: Cc1nc2cc(C(=O)NC(C)C)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)c2nc1C
Yield: 42 %

Procedure:
See step f) of example H2 for the reaction conditions starting from 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6,7-dimethyl-3-oxa-1,5,8-triaza-anthracen-4-one and 2 equivalents of isopropylamine. After 18 hours reaction time and purification by flash chromatography on silica gel, a white solid is obtained within 42% yield. m.p.: 243-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:28]=1[CH2:29][N:30]([C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[S:31]([C:34]1[CH:39]=[CH:38][C:37](F)=[C:36]([F:41])[CH:35]=1)(=[O:33])=[O:32]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:37]2[CH:38]=[CH:39][C:34]([S:31]([N:30]([CH2:29][C:28]3[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:27]=3[O:26][CH3:25])[C:42]3[N:43]=[CH:44][CH:45]=[CH:46][N:47]=3)(=[O:32])=[O:33])=[CH:35][C:36]=2[F:41])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Reactant: O=c1[nH]c2cc(-c3cc(Cl)ccc3O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3ccc4oc(=O)[nH]c4c3)c(F)c2)c(OC)c1
Temperature: 75 °C

Procedure:
To a mixture 5-(5-chloro-2-hydroxyphenyl)benzo[d]oxazol-2(3H)-one (0.068 g, 0.26 mmol) and potassium carbonate (0.054 g, 0.39 mmol) in dimethylsulfoxide (2 mL) was added N-(2,4-dimethoxybenzyl)-3,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (0.114 g, 0.27 mmol). The reaction mixture was heated at 70-80° C. for 16 h, allowed to cool to ambient temperature and partitioned between ethyl acetate (100 mL) and water (10 mL). The organic phase was washed with brine (2 5 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-100% gradient of ethyl acetate in hexanes to give 4-(4-chloro-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-3-fluoro-N-(pyrimidin-2-yl)benzenesulfonamide as an orange solid which was carried forward without further purification: MS (ES+) m/z: 662.9 (M+1), 664.9 (M+1)
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: NCCCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 4-aminobutanol to produce [2-(4-hydroxybutyl]amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(4-hydroxybutyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 4-(3,5-dioxomorpholino)butyl methanesulfonate and (d) reacting the mesylate with 3[bis(4-butoxy-o-tolyl)methyl]piperidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([N:6]2[C:10]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=3[OH:21])=[CH:9][CH:8]=[N:7]2)[CH2:3]1.CC(C)([O-])C.[K+].[S:28]1[CH:32]=[C:31]([N:33]([S:41]([C:44]2[CH:49]=[C:48]([F:50])[C:47](F)=[CH:46][C:45]=2[F:52])(=[O:43])=[O:42])C(=O)OC(C)(C)C)[N:30]=[CH:29]1.O>C(#N)C>[F:52][C:45]1[CH:46]=[C:47]([O:21][C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[C:10]2[N:6]([CH:4]3[CH2:3][N:2]([CH3:1])[CH2:5]3)[N:7]=[CH:8][CH:9]=2)[C:48]([F:50])=[CH:49][C:44]=1[S:41]([NH:33][C:31]1[N:30]=[CH:29][S:28][CH:32]=1)(=[O:43])=[O:42]
Reactant: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2F)C1
Reaction time: 0.5 h

Procedure:
2-[1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenol, (Preparation 855, 137 mg, 0.00046 mol) was dissolved in acetonitrile (10 mL) and treated with potassium tert-butoxide (57 mg, 0.0005 mol) and stirred under nitrogen for 30 minutes. Tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation 297, 182 mg, 0.00046 mol) was added and the solution stirred for 2 hours. Water (0.2 mL) was added and the solution evaporated. The residue was suspended in water and extracted with ethyl acetate (1×20 mL). The organic layer was separated and washed with brine (2×20 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give a foam. The foam was purified using an ISCO™ Companion (4 g. silica gel, eluting with dichloromethane:acetic acid 99.5:0.5 to dichloromethane:methanol:acetic acid 95:5:0.5). The appropriate fractions were evaporated to give a film. The film was triturated with diethyl ether to give the title compound as a white solid (11 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.145 g, 0.767 mmol) and 6-methyl-3-(piperidin-4-yl)-1H-indole (0.150 g, 0.697 mmol) using ethanol as reaction solvent. Yield 0.140 g (49%) as a tan foam. FDMS m/e=403 (M+ of free base). α[D]589 =+3.8 (c=0.98, dimethylsulfoxide).
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>COCCOC>[N:48]1([C:11]2[N:41]=[CH:40][N:39]=[C:38]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C@@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:17]2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and dry DME (1.0 mL). Morpholine (17.5 μL, 0.200 mmol) was added, the reaction mixture was flushed with N2, and the mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The mixture was washed with 10% aq citric acid, sat aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. No additional purification was needed and 43 mg (78% yield) of the title compound was obtained. Rf (3% MeOH in CH2Cl2)=0.18. 1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H, Ar—H), 8.02 (s, 1H, Ar—H), 6.46 (t, 1H, H-1′, J=6.6), 4.59 (m, 1H, H-3′), 4.30 (br s, 4H, 2CH2), 4.01 (app q, 1H, H-4′, Japp˜3.4), 3.85-3.82 (m, 5H, H-5′ and 2CH2), 3.76 (dd, 1H, H-5′, J=11.0, 3.2), 2.59 (app quint, 1H, H-2′, Japp˜6.5), 2.42 (ddd, 1H, H-2′, J=13.2, 5.9, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08, 0.076 (3 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.9, 152.3, 150.6, 136.8, 120.4, 87.8, 84.1, 72.0, 67.0, 62.8, 45.6, 41.1, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C26H48N5O4Si2 (M++H) 550.3245. found 550.3222.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCCC1)([O:17][C:18](C)(C)[CH3:19])=O>>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:19][CH2:18][OH:17])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Product: CC(C)(C)OC(=O)N1CCCCC[C@@H]1CCO

Procedure:
This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-hexahydroazepine is used insead of 1-Boc-pyrrolidine.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>CN(C)C=O>[NH:32]([C:30]([CH2:29][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)Nc1ccccc1
Reaction time: 48 h

Procedure:
4-Amino -1-(4-phenyl-4-oxobutyl) piperidine dihydrochloride (1.75g) was suspended in dimethylformamide (15 ml) containing triethylamine (3 ml) and chloroacetanilide (0.85G) added. The mixture was stirred for 48 hours and the precipitate of Et3N.HC1 filtered off. The filtrate was poured into water and the solid product filtered off and recrystallised from EtOH/H2O to give the title compound (1.35g). This was converted to the hydrochloride (1.35g) by treatment with EtOH-HC1 and Et2O, m.p. 255.1°.
Reaction SMILES: [ClH:1].[N:2]1([NH2:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>CC(O)=O.O>[ClH:1].[N:2]1([N:12]=[C:13]2[CH2:18][CH2:17][CH2:16][C:15]([OH:19])=[CH:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCC(=O)C1
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC1=CC(=NN2CCCc3ccccc32)CCC1
Temperature: 40 °C
Yield: 69.1 %

Procedure:
3,4-Dihydro-1(2H)-quinolinamine hydrochloride (5.0 g, 27 mmol) and 1,3-cyclohexanedione (3.1 g, 27 mmol) was mixed in AcOH (4.3 mL) and H2O (4.3 mL). The mixture was heated at 40° C. for 10 min until dissolved completely. The mixture was then concentrated to dryness. The residue was washed with acetonitrile then filtered to yield 3-(3,4-dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (5.2 g, 69%) as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15]O)=[CH:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>N1C=CC=CC=1.ClCCl>[Cl:3][CH2:15][C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=2[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2sc(CO)cc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (1.0.ml) was added dropwise to a stirred mixture of 5-nitrobenzo[b]thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours and then washed with water followed by aqueous sodium bicarbonate solution, and then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave a solid which was crystallised from ethyl acetate to give the title compound (0.73 g), m.p. 110°-112°, used directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[CH:23][C:22]([C:36]([F:39])([F:38])[F:37])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.O>C(#N)C.CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)=[CH:23][C:22]([C:36]([F:37])([F:38])[F:39])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a solution of methyl 4-amino-2-fluorobenzoate (870 mg, 5.143 mmol) in acetonitrile was added DMAP (691 mg, 5.657 mmol) and phenyl (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (2036 mg, 5.143 mmol) at room temperature. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added water and extracted with EtOAC. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography to give pure methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (1.3 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:17]([CH2:21][C:22]#[CH:23])[C:18](=O)[CH3:19])(C)(=O)=O>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COCOc1cccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(O)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A solution of 2-amino-3-methoxymethoxypyridine (7.5 g) and 3-mesyloxy-5-hexyn-2-one (10.18 g), in ethanol (150 ml) was refluxed for 46.5 hours and then evaporated in vacuo. To the residue was added 20% sulfuric acid (75 ml) and the mixture was stirred for 5 hours at room temperature. The mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with chloroform and then a mixture of chloroform and methanol (30:1 to 20:1) as eluents. The eluates were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.93 g).