Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([N:13](CC)CC)C.N[C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[C:30]2[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:40][C:39]=3[C:9]3[CH:8]=[CH:7][C:3]([C:4]([NH2:13])=[O:5])=[C:2]([CH3:1])[CH:10]=3)=[O:24])[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2C(=O)N2CCc3cccn3-c3ccccc32)ccc1C(N)=O

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]-[1,5]benzodiazepine. The reaction mixture is washed with water, 2M citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (CI): 422 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:32])[CH3:31])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][N:16]([C:18](OCC1C=CC=CC=1)=O)C)([CH3:3])[CH3:2].[CH3:34]O>[Pd]>[C:1]([O:4][C:5](=[O:33])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:32])[CH3:31])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][NH:16][CH3:18])([CH3:2])([CH3:3])[CH3:34]
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OC(C)C)C(=O)NCCN(C)C(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: CNCCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(C)=O
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of compound I (1.4 g, 3.00 mmol) in MeOH (40 mL) was added 5% Pd/C (300 mg). This reaction mixture was subjected to hydrogenation at 70 psi for 2 h. Next, the reaction mixture was filtered through a celite pad, MeOH was removed in a rotary evaporator to afford compound J (1.02 g, 98%). LC-MS [M+H] 344.9 (C16H32N4O4+H, calc: 345.4).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[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:54])[C@H:46]([CH2:48][CH2:49][C:50]([O:52]C)=[O:51])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:47][C@H:46]([C:45]([OH:44])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:36])=[CH:38][CH:39]=2)=[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: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 233 and L-glutamic acid dimethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.33-12.71 (br.s, 1 H), 11.89-12.26 (br.s, 1 H), 8.94 (s, 1 H), 8.12 (d, 1 H), 7.23 (m, 7 H), 6.99 (m, 7 H), 6.82 (d, 2 H), 4.22 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.28 (m, 4 H), 1.95 (m, 3 H), 1.77 (m, 1 H); MS (ESI+) m/z 704 (M+H)+.
Reaction SMILES: C([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][C:21]2[CH:45]=[CH:44][C:24]([C:25]([C:27]3[C:28](CCCC(OCC)=O)=[CH:29][N:30]4[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]4)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18][CH3:19])=[C:11]([F:46])[CH:10]=1)[CH:6]([CH3:8])[CH3:7])(=O)C.[OH-].[Na+].[C:49]([O:52]CC)(=[O:51])[CH3:50].Cl.[CH2:56](O)[CH3:57]>O1CCOCC1>[F:46][C:11]1[CH:10]=[C:9]([CH:5]([OH:4])[CH:6]([CH3:7])[CH3:8])[CH:14]=[CH:13][C:12]=1[CH:15]([O:20][C:21]1[CH:45]=[CH:44][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH2:56][CH2:57][CH2:50][C:49]([OH:52])=[O:51])[N:30]3[C:35]=2[CH:34]=[CH:33][CH:32]=[CH:31]3)=[O:26])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCO
Reactant: CCCCC(Oc1ccc(C(=O)c2c(CCCC(=O)OCC)cn3ccccc23)cc1)c1ccc(C(OC(C)=O)C(C)C)cc1F
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCC(Oc1ccc(C(=O)c2cc(CCCC(=O)O)n3ccccc23)cc1)c1ccc(C(O)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-[1-[4-[1-[4-(1-acetoxy-2-methylpropyl)-2-fluorophenyl]pentyloxy]benzoyl]indolizin-yl]butyrate (300 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1N aqueous solution of sodium hydroxide (1.5 ml). The mixture was stirred at room temperature for 1 hour, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of chloroform and methanol (25:1) to give 4-[1-[4-[1-[2-fluoro-4-(1-hydroxyl-2-methylpropyl)phenyl]-pentyloxy]benzoyl]indolizin-3-yl]butyric acid (151 mg) as powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][C:31]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][C:31]4([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: NC1(CO)CCCC1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NC3(CO)CCCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and 1-amino-1-cyclopentanemethanol gave 174. MS: (ESI+) 511.0
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].[C:15](=[O:18])([O-:17])[O-].[Na+].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[C:15]([NH:6][C@H:2]([C:3]([OH:5])=[O:4])[CH2:1][S:7][S:8][CH2:9][C@H:10]([NH:14][C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C:11]([OH:13])=[O:12])([O:17][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:18]
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](CSSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 10 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Fmoc-protected cysteine (FIG. 3, structure B) was synthesized in a two step sequence from L-cystine as outlined in FIG. 4. Sodium carbonate (4.6 g, 43.6 mmol) and L-cystine (5.0 g, 20.8 mmol) were dissolved in water (200 mL). The resulting solution was cooled to 10° C. FmocCl (11.85 g, 45.8 mmol) was dissolved in dioxane (80 mL), and the resulting solution was added dropwise to the aqueous solution of L-cystine. The solution was stirred for 2 h at 10° C. and allowed to gradually warm to room temperature. A thick white precipitate was obtained that was filtered onto a sintered glass funnel. The product was triturated with diethyl ether (50 mL) and dried in vacuuo for 2 d. N,N′-Bis(Fmoc)-L-cystine (14.0 g, 98% yield) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21]([NH2:23])=[S:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C[Si](C)(C)Cl.C(N(CC)CC)C>C(#N)C.O>[CH:36]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:43])=[CH:26][N:35]=3)[C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[C:32]2[N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21]([NH2:23])=[S:22])[O:16][C:15]4=[O:24])=[CH:3][C:2]=3[F:1])[CH2:9][CH2:10]2)[CH2:37][CH2:38]1
Reactant: NC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: NC(=S)NC[C@H]1CN(c2ccc(N3CCN(c4c(C(=O)O)c(=O)c5cc(F)cnc5n4C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 29.8 %

Procedure:
A mixture of 100 mg [(5S)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-thiourea (0.28 mmol), 87.98 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.31 mmol), 71.57 μl trimethylchlorosilane (0.56 mmol) and 118.31 μl triethylamine (1.4 mmol) in acetonitrile was stirred in a micro wave oven for 8 min at 150° C. The reaction mixture was diluted with water and the solid filtered. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture with 1% acetic acid as eluent to leave 50 mg of an oily residue which was crystallized from a ETOAC/hexane mixture.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:28]>C(#N)C.C(OCC)(=O)C.CCCC(C)C>[Cl-:25].[CH3:36][C:33]1[N:32]=[CH:31][C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])=[CH:35][CH:34]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: Cc1ccc(NC(=O)CCl)cn1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)cn1
Product: [Cl-]
Reaction time: 240 h
Yield: 44.8 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 1e)(52 mg) was dissolved in acetonitrile (2 mL) and 2-chloro-N-(6-methylpyridin-3-yl)acetamide (Example f) (29 mg) was added. The reaction mixture was stirred for 10 days and diluted with ethyl acetate (4 mL) and isohexane (14 mL). The mixture was left standing for 5 days, whereupon the resulting crystals were separated and washed with diethyl ether (0.5 mL) to afford the titled compound as a solid (36 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Cc1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115 mg, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL) was added p-toluidine (46 mg, 0.43 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (94 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[O:14][B:15](OC)[O:16]C.[C:20]12([OH:31])[CH2:28][CH:24]([C:25]1([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]2([OH:30])[CH3:29]>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1.[C:20]12([OH:31])[CH2:28][CH:24]([C:25]1([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]2([OH:30])[CH3:29]
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: COB(OC)OC
Agent: CC1(O)CCC2CC1(O)C2(C)C
Product: OB(O)c1cccc(C2OCCO2)c1

Procedure:
Synthesis of compounds 16 and 21 are as previously described above. As detailed below, with reference to Scheme 3 and examples 20 and 21, below, the synthesis of compound 26 is described. (+)-pinanediol (1R)-1-acylamino-1-(3-formylphenyl)methylboronates 25, 26 were obtained starting from commercial 2-(3-bromo-phenyl)-[1,3]dioxolane (22a), following the same procedure. Metallation of 22a with buthyllithium at −78° C., followed by reaction with trimethylborate and transesterification with (+)-pinanediol, afforded the desired (+)-pinanediol (3-[1,3]dioxolan-2-yl-phenyl)boronate (+)-23a together with variable amount of (+)-pinanediol (3-dimethoxymethyl)phenylboronate (+)-23b, this latter probably formed by transacetalization with the in situ formed methanol. To avoid this problem, 22a was converted to 22b (88%) and subsequently boronated to (+)-23b (75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=4)[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
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: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(O)cc2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (1.5 g, 4.6 mmol), (4-hydroxyphenyl)-boronic acid (0.768 g, 5.56 mmol) and Pd(PPh3)4 (0.536 g, 0.464 mmol) in 1,4-dioxane (15 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (1.77 g, 16.7 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford methyl 1-cyclopentyl-6-(4-hydroxyphenyl)-1H-indazole-4-carboxylate (1.1 g, 71%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>>[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.2 mol of 2-(4-bromobutyl)isoindole-1,3(2H)dione and 0.2 mol of 1-(2-pyrimidyl)piperazine are stirred with 0.2 mol of K2CO3 at 120°-130° C. under an atmosphere of N2 overnight. The mixture is then evaporated to dryness. Water is added and the residue is taken up in methylene chloride. After drying the organic solution, it is evaporated to obtain an oil which crystallises on trituration with cyclohexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]I)=[N:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([S:17]([CH2:20]C)(=[O:19])=[O:18])[CH3:16])[CH3:12].BrC1C=NC=CC=1.BrC1C=CC(CCC(C)(S(C)(=O)=O)C(OCC)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:15]([CH3:16])([S:17]([CH3:20])(=[O:18])=[O:19])[C:14]([O:13][CH2:11][CH3:12])=[O:22])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)S(=O)(=O)CC
Reactant: Brc1ccc(CCI)nc1
Agent: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Solvent: Brc1cccnc1
Product: CCOC(=O)C(C)(CCc1ccc(Br)cn1)S(C)(=O)=O
Yield: 48.5 %

Procedure:
The title compound (2030 mg, 49%) was prepared from 5-bromo-2-(2-iodoethyl)pyridine (3571 mg, 11.5 mmol) and (+/−)-2-ethanesulfonyl-propionic acid ethyl ester (2270 mg, 12.6 mmol) by a procedure analogous to that described for the preparation of compound (1) from Preparation 2, Step 2, i.e. (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate. MS (LC MS) m/z 364.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.03 Hz, 3H) 1.68 (s, 3H) 2.28-2.39 (m, 1H) 2.54-2.76 (m, 2H) 2.83-2.95 (m, 1H) 3.05 (s, 3H) 4.24 (q, J=7.29 Hz, 2H) 7.05 (d, J=8.59 Hz, 1H) 7.71 (dd, J=8.20, 2.34 Hz, 1H) 8.56 (d, J=1.95 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:17][CH2:16][CH2:14][OH:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Product: O=S(=O)(NCCO)c1cc(Br)c(F)cc1F
Yield: 98.6 %

Procedure:
Prepared by general procedure III from 5-bromo-2,4-difluorobenzene sulfonyl chloride (1.0 g, 3.4 mmol) and ethanolamine (231 mg, 3.77 mmol) to give the title compound (1.06 g, 100%) as an off-white solid. MS (ISP) 315.8 [(M+H)+].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:31])[C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:31])[C:18]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2c(Cl)cc(OCc3ccccc3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A stirred solution of 10.0 grams (0.046 mole) of tert-butyl 4-(hydroxymethyl)piperidinecarboxylate (commercially available) and 12.5 grams (0.046 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) in 100 mL of THF was cooled in an ice-water bath and 12.2 grams (0.046 mole) of triphenylphosphine was added in one portion. Upon completion of addition 9 mL (0.046 mole) of diisopropyl azodicarboxylate was added dropwise during a five minute period. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 21 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O1CCCC1.O>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask was mixed tert-butyl 4-(5-(ethoxycarbonyl)thiophen-2-yl)piperidine-1-carboxylate (5.00 g, 14.73 mmol) in tetrahydrofuran (50 ml). Aqueous 4N NaOH (38.41 ml, 73.6 mmol) solution was added along with some methanol (10 ml) to get a single phase solution. The mixture was stirred overnight at room temperature. The solvents were removed to give a white slurry that was diluted with water and adjusted to pH of 5 with 1N aqueous hydrochloric acid. Filtration provided the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:13]([CH3:14])[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:13]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[CH2:4][CH2:3][CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: Cn1c(CCCO)nc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 750 mg of 2-(3-hydroxypropyl)-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 34), 1.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.98 ml of tributylphosphine, 990 mg of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume as the eluent, to give 550 mg of the title compound, melting at 76-81° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].CC(C)=O.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br-:1].[Br:12][CH:11]([N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: BrCCCCCCCCCCBr
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCC(Br)[n+]1ccccc1
Product: [Br-]
Temperature: 45 °C

Procedure:
To a vigorously stirring flask of 1,10-dibromodecane (337.2 mL; 1.5 mmol) was added pyridine in acetone (50 vol. %; 16.2 mL; 0.1 mmol) dropwise over 5 hours at 30° C. After the addition was complete, the mixture was heated to 45° C. for 18 hours. The reaction mixture was allowed to cool slightly and the resulting white precipitate was filtered over a Buchner funnel. The product was washed thoroughly with hexanes (3×100 mL) and vacuum dried. The product was identified by 1H NMR and mass spectrometry.