Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C)C(=O)C>[CH3:45][S:46]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1)(=[O:48])=[O:47]
Reactant: OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 1 °C

Procedure:
To a mixture of 5-(4'-hydroxymethyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (0.01 m=4.90 g) and potassium carbonate (0.05 m=6.90 g) stirred in 50 mL N,N-dimethylacetamide chilled at 1° C. was added a total of 3.34 g (0.024 m) of methanesulfonyl chloride in portions over 6 hours. The progress of the reaction was monitored by thin layer chromatography or HPLC. The title compound was formed in better than 90% in the mixture which was used in the next example.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11]OC)[C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].BrC[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH:4]([C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][CH2:11][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: COCOc1cccc(O)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxy-6-methoxymethoxybenzaldehyde (0.91 g, 5.1 mM) in dry dimethyl sulphoxide (8 ml) was added potassium t-butoxide (0.57 g, 5.1 mM) with exclusion of moisture. After 10 mins, ethyl 4-bromomethylbenzoate (1.22 g, 5 mM) was added and the whole stirred at room temperature (18 hrs). The reaction mixture was poured into water (100 ml) and the liberated oil extracted into ether. The combined extracts were washed with 5% sodium carbonate solution, water, dried (sodium sulphate) and evaporated. The residual oil (ethyl 4-(2-formyl-3-methoxymethoxyphenoxymethyl)benzoate was dissolved in ethanol (30 ml) and treated with 3 M hydrochloric acid (30 ml) with stirring at 60° C. (30 mins). The solid was filtered off, washed with water, dried, and recrystallised from ethanol/water to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-ω° C. (identical to a sample previously prepared, Example 5(B)).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O-:14])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:9]2[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=2)[CH2:17][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ncc(C(=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Yield: 80 %

Procedure:
Using a procedure analogous to Example B27, 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B27 (0.30 g, 1.24 mmol) and tert-butyl piperazine-1-carboxylate (1.15 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylic acid (0.36 g, 80% yield). MS (ESI) m/z: 365.0 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23]O)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:25])[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]4)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:25])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C1CNC1
Reactant: Cc1cc(-c2nc(-c3ccc(CO)nc3C)no2)ccc1CC(C)C
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)c(C)n2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-methylpyridin-2-yl}methanol (0.14 g, 0.43 mmol) that was obtained in Example 27 (27e), carbon tetrabromide (0.29 g, 0.86 mmol), triphenylphosphine (0.23 g, 0.86 mmol), methyl 3-azetidinecarboxylate hydrochloride (98 mg, 0.65 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:1 to 3:1) as the eluent to afford the title compound (0.12 g) in a yield of 66% as a colourless oily product.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:47][C@H:46]([C:45]([OH:44])=[O:51])[CH:48]([CH3:50])[CH3:49])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N[C@H](C(=O)O)C(C)C)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and L-valine methyl ester hydrochloride (34 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.03-12.85 (br.s, 1 H), 8.95 (s, 1 H), 7.96 (d, 1 H), 7.23 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.68 (dd, 1 H), 6.49 (m, 2 H), 4.14 (dd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.92 (t, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.31 (m, 2 H), 2.02 (m, 1 H), 1.90 (m, 2 H), 0.86 (s, 3 H), 0.85 (s, 3 H); MS (APCI+) m/z 674.7 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: CCCCN
Product: CCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and butylamine (2 ml) the subtitle compound was obtained (563 mg, 100%). MS 388 m/z (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH3:14]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at 0° C. for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford (3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4%] as an oil, which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.95 min; [M+H]+=395.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:36]=5[C:35]=4[CH:37]=3)[CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1ccc2sc3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3ccc4sc5ccccc5c4c3)c2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture solution of bis(3-bromophenyl)diphenylsilane (10.84 g, 21.92 mmol), dibenzo[b,d]thiophen-2-yl boronic acid (2.000 g, 8.77 mmol), Pd(PPh3)4 (0.101 g, 0.088 mmol) and K2CO3 (2.424 g, 17.54 mmol) in toluene (200 mL) and water (50 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9:1, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-2-yl)phenyl)diphenylsilane (3.16 g, 60% yield) as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:29][C:30]([CH3:33])=[CH:31][N:32]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:28]4[C:27]([CH3:26])=[N:32][CH:31]=[C:30]([CH3:33])[N:29]=4)[CH2:35][CH2:36]3)=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3Cl)CC2)n1

Procedure:
In analogy to example 1,1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 555.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[C:15]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[O:37][CH:38]([F:40])[F:39])=[N:14]1.[BH3-]C#N.[Na+]>C1COCC1>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([O:37][CH:38]([F:40])[F:39])=[C:30]([C:15]2[C:16]([NH:18][C:19]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[N:26][C:25]=34)=[O:20])=[CH:17][N:13]([CH2:12][CH2:11][NH:10][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=3)[N:14]=2)[CH:35]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cn(CCNCc2ccc(O)cc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-hydroxybenzaldehyde (55 mg, 0.45 mmol) and N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in THF (10 mL) was stirred at room temperature for 2 h and then NaBH3CN (28 mg, 0.45 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 0.1 mL of water. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 3% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (34.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.4 mg (23%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 20) [M+H]+=554.2, RT=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.10 (d, 2H, J=8.4 Hz), 7.06 (t, 1H, J=73.2 Hz), 6.68 (d, 2H, J=8.4 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.63 (s, 2H), 2.95 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][N:2]([CH2:12][CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CN(CC1CCNCC1)C(=O)NC1CCCCC1
Yield: 54.4 %

Procedure:
1-Methyl-1-(4-pyridylmethyl)-3-phenylurea (7.0 g) in glacial acetic acid (50 ml) was hydrogenated over platinum oxide at 60°/60 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The resultant oil was basified with 5 N NaOH (to pH 12) and extracted with chloroform (2×50 ml). The combined extracts were dried (MgSO4) and evaporated with chloroform (2×50 ml). The combined extracts were dried (MgSO4) and evaporated to give 1-methyl-1-(4-piperidylmethyl)-3-cyclohexylurea as an oil (4.0 g). The n.m.r. and mass spectra were compatible with the required structure.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CO[C@H]1C[C@@H](C(=O)Nc2ccc(F)nc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CN[C@H](C(=O)Nc2ccc(F)nc2)C1
Yield: 93.3 %

Procedure:
To a stirred suspension of palladium on carbon (10%, 80 mg) in methanol (100 mL) was added a solution of (2S,4S)-benzyl 4-methoxy-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 62A (400 mg, 1.12 mmol) in methanol (100 mL) under nitrogen. The suspension was hydrogenated with a hydrogen balloon atmosphere overnight. The resulting suspension was filtered through a pad of celite and washed with methanol. Concentration of the filtrate gave the product as an oil (250 mg, 100%) which was used without purification in the next step. LC/MS [M+H]+: 240; Ret time (Method F): 0.91 min.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:32]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H](O)C1)(=O)C(C)C>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:32]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:46][CH:45]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound was prepared from thymidine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=O)[CH2:18][C:19](=[O:21])[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=[S:36])[CH2:18][C:19](=[O:21])[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanoyl)pyrrolidine-2-carboxylate (example 375b) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) to give the title compound as orange foam. MS (ESI): m/z=421.9 [M+H]+.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>O.C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Sodium (3.802 g, 165.38 mmol, 2.5 eq) was added portionwise into ethanol (66 mL, 1M) at 0° C. Next, 3-nitro-ortho-xylene (10.00 g, 66.15 mmol, 1 eq) and diethyl oxalate (19.33 g, 132.23 mmol, 2 eq) were added. The mixture was stirred at room temperature for 18 hours and then refluxed for 10 minutes. 1N sodium hydroxide and water were added and the reaction was stirred for one hour. The ethanol was removed under vacuum. Water was added and the aqueous solution was acidified with concentrated hydrochloric acid to ph~2. The mixture was extracted with methylene chloride. The extracts were dried (magnesium sulfate) and concentrated to give the title compound (9.0 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>CC(C)=O>[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add 4-aminobenzonitrile (3.125 g, 26.4 mmol) and potassium carbonate (8.04 g, 58.2 mmol) to a solution of 4-chloromethyl-benzoyl chloride (5.00 g, 26.4 mmol) in acetone (60 mL). Heat at reflux for 4 hours. Cool to room temperature, filter, and concentrate to afford the title compound as a yellow solid (7.30 g, 91%): 1H NMR (DMSO-d6) δ 4.86 (s, 2H), 7.61 (d, 2H), 7.83 (d, 2H), 7.94-8.03 (m, 4H), 10.72 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N1CCC(C2C=CC(Cl)=CC=2)(C)CC1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.ClC1C=CC(C2(C)CCNCC2)=CC=1>CO>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: CC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Product: CC1(c2ccccc2Cl)CCNCC1

Procedure:
The mixture of 1-benzyl-4-(2-chloro-phenyl)-4-methylpiperidine and 1-benzyl-4-(4-chloro-phenyl)-4-methyl-piperidine (1.6 g) was dissolved in methanol (30 mL) and 1-chloroethylchloroformate (0.9 mL) was added. The mixture was heated at reflux for 10 minutes and allowed to cool. The solvent was removed by evaporation under vacuum and the residue precipitated from ethyl acetate with ether to give a 4:1 mixture of the title compound and 4-(4-chloro-phenyl)-4-methyl-piperidine which was used directly without further purification. LCMS m/z 210.2 [M+H]+. R.T.=2.64 min (Analytical Method 4).