Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COCc1cnc(C(=O)OC)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
A mixture of dimethyl 5-(methoxymethyl)-2,3-pyridinedicarboxylate (60.0 g, 0.25 mol) and 50% sodium hydroxide solution (50.0 g, 0.63 mol) in water is heated at 90-110° C. for 2 hours under nitrogen while distilling off methanol and water. The reaction mixture is cooled to 10° C., treated with sulfuric acid to adjust the pH to 2.0 and filtered to obtain a solid. The solid is washed with water and vacuum dried to give the title product as a white solid (44.3 g, mp 161-162° C.).
Reaction SMILES: [S:1](=[O:29])(=[O:28])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([C:22](=[O:27])[NH:23][CH2:24][CH2:25]C)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].S(=O)(=O)(OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C=CC4)CCC=2C=1)N>>[S:1](=[O:28])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([C:22](=[O:27])[NH:23][CH2:24][CH3:25])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(OS(N)(=O)=O)ccc3[C@H]1CC2
Product: CCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
In similar manners to those described for the synthesis of compound 7, compound 29g was prepared from compound 11g. FAB-MS m/z 407 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.60 (s, 3H, CH3), 1.01 (t, 3H, J=7.3 Hz, CH2CH3), 3.02 (m, 1H, CH2CH3), 3.16 (m, 1H, CH2CH3), 6.96 (d, 1H, J=2.0 Hz, ArH), 7.01 (d, 1H, J=8.6 Hz, ArH), 7.34 (d, 1H, J=8.6 Hz, ArH), 7.47 (t, 1H, J=5.6 Hz, NHCH2), 7.87 (s, 2H, NH2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](O)=[O:19])[C:12]1=[O:21].[Cl-].[Na+]>ClCCl.Cl>[OH:19][CH2:18][CH2:17][C:13]1[C:12](=[O:21])[N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reaction time: 16 h
Yield: 83.8 %

Procedure:
At 20° C., over the course of 20 min, 56.8 g (348 mmol) of borane-dimethylaniline complex were added dropwise to a solution of 50 g (174 mmol) of [1-(2-methyl-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]acetic acid in 100 ml of 2-methyl-THF. The mixture was after-stirred for 16 h and diluted with 500 ml of dichloromethane. Over the course of 30 min, this mixture was metered into a solution of 50 g of sodium chloride in 500 ml of 1M hydrochloric acid. The mixture was after-stirred for 1 h and the organic phase was washed again with 500 ml of a solution of 50 g of sodium chloride in 500 ml of 1M hydrochloric acid. Washing with 500 ml of a saturated aqueous sodium hydrogen carbonate solution, drying over sodium sulphate and evaporation were carried out. 40 g (84%) of the desired alcohol were obtained.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[Cl-].[Ca+2].[Cl-].[CH3:7][N:8](C)[CH:9]=[O:10].C(Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]C#N.[Na+]>CN(C)C=O>[CH2:7]([N:8]=[C:9]=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccccc1
Agent: N#C[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C=NCc1ccccc1

Procedure:
100 g of anhydrous calcium chloride powder was added to 100 g of dimethylformamide with agitation, and the mixture was heated to form a paste. The paste was evaporated to dryness under a reduced pressure and below 50°C. to obtain a coarse white crystalline powder. Analysis showed that the powder was a calcium chloride-dimethylformamide compound. 20 g of this white crystalline powder was dissolved in 300 g of dimethylformamide, and 126.6 g of benzyl chloride was added to the solution and 75 g of sodium cyanate powder (having a purity of 98 %) was added to the solution with agitation, at an elevated temperature of 100°C., over a period of 4 hours. When 5 hours had passed from the start of the reaction, the reaction mixtures was treated under reduced pressure to recover dimethylformamide by distillation, and the residue was extracted with benzene and the benzene extract was distilled under reduced pressure to obtain 113 g of benzyl isocyanate (the yield being about 85 %). When the above reaction was repeated without adding 20 g of the white crystalline powder, tribenzyl isocyanurate was obtained in a yield of about 70 %, instead of benzyl isocyanate.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15](=[O:27])[NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>CO>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][NH:16][C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)=[O:27])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Yield: 91 %

Procedure:
Compound 31 was dissolved in MeOH (20 ml) and 2 M aqueous NaOH (10 ml) was added. The reaction mixture was stirred at room temperature for 2 h until no compound 31 was detected by TLC. The reaction solution was evaporated to about 8 ml and adjusted to pH 3 with 2 M HCl. The precipitates formed were collected by filtration or centrifugation, washed with water and dried under high vacuum to give a white powder (0.158 g) in total yield of 91%. MS 346.23 (M−H+). 1H NMR (DMSO-d6) 11.95 (s, 1H), 8.36 (t, 1H), 8.18 (s, 1H), 7.72 (d, 1H), 7.41 (d, 1H), 7.15 (s, 1H), 6.91 (t, 1H), 3.29 (q, 2H), 3.10 (q, 2H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.Cl[C:19]1[C:24]([CH2:25][CH3:26])=[N:23][CH:22]=[C:21]([CH2:27][CH3:28])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH2:25]([C:24]1[C:19]([NH:1][C@H:2]2[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3]2)=[N:20][C:21]([CH2:27][CH3:28])=[CH:22][N:23]=1)[CH3:26]
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCOCC
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
A 250 ml round bottom flask was charged with benzyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.97 g, 21.04 mmol), 2-chloro-3,6-diethylpyrazine (3.95 g, 23.15 mmol), Pd2(dba)3 (10 mol %, 1.926 g), 2-dicyclohexylphosphino-2′-(N, N-dimethyl amino)biphenyl (20 mol %, 1.66 g), ethylene glycol dimethyl ether (110 mL), and Cs2CO3 (9.57 g) respectively. The reaction mixture was stirred at 80° C. for 20 hr. It was cooled, diluted with Et2O (100 ml), poured into NaHCO3 (80 ml), extracted with CH2Cl2 (150 ml×3), dried (MgSO4), and concentrated. Purification with Biotage MPLC (35% EtOAc in heptane) provided 4.6 g (60%) of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2969, 2344, 1996, 1952, 1703, 1691, 1546, 1499, 1449, 1426, 1395, 1359, 1175, 1133, 1095, cm−1. HRMS (FAB) calcd for C20H26N4O3+H1 371.2083. found 371.2089.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:18]([OH:33])[C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41]=O>>[CH2:1]([N:8]([CH3:41])[C@H:9]([C:14]([NH:16][C@@H:17]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@H:18]([OH:33])[C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NCc1ccccc1
Reactant: C=O
Product: CN(Cc1ccccc1)[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C
Yield: 73.2 %

Procedure:
Following a procedure similar to that described in Example 67, but using 200 mg (0.36 mmol) of 1-[(2S,3S)-3-(N2 -Benzyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 86) and 41 μl (0.54 mmol) of 37% formalin, 149 mg of the title compound were obtained as a colorless powder, melting at 97°-100° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.I[C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:15]2[CH:16]=[C:17]([N:1]3[CH:5]=[CH:4][C:3]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=4)=[CH:2]3)[CH:18]=[CH:13][CH:14]=2)[CH:20]=1
Reactant: Ic1cccc(-c2cccnc2)c1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccn(-c3cccc(-c4cccnc4)c3)c2)nc1
Temperature: 110 °C

Procedure:
A solution of 2-(1H-pyrrol-3-yl)pyridine (0.144 g, 1.0 mmol), 3-(3-iodophenyl)pyridine (0.281 g, 1.2 mmol), 1,10-phenanthroline (0.360 g, 2 mmol), Potassium phosphate (0.445 g, 2.1 mmol), in dioxane (3 mL) was degassed with argon for 5 minutes, followed by the addition of copper (I) iodide (0.038 g, 0.2 mmol). The reaction mixture was heated at 110° C. for 4 hr. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 2-[1-(3-pyridin-3-ylphenyl)-1H-pyrrol-3-yl]pyridine as a slightly yellow oil. The free base in anhydrous diethyl ether was treated with 1.5 equivalents HCl (1M in ether) to give the HCl salt.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1
Reactant: CC1CCNC(C(=O)O)C1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1CCNC(C(=O)OCc2ccccc2)C1
Yield: 22 %

Procedure:
A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160°-163° C.
Reaction SMILES: C1(C[O:8][C:9](=[O:43])[C@@H:10]([NH:19][C@@H:20]([CH3:42])[C:21](=[O:41])[O:22][C@@H:23]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24](=[O:33])[O:25]CC2C=CC=CC=2)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.[Pd]>[C:24]([C@@H:23]([O:22][C:21](=[O:41])[C@@H:20]([NH:19][C@@H:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:43])=[O:8])[CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:33])=[O:25]
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The product of step b) (0.5 g) in ethyl acetate (30 ml) and trifluoroacetic acid (2 ml) was hydrogenated at 1 bar over 10% palladium on charcoal for 1 day. The catalyst was filtered off, the solvent evaporated and the residue purified by reverse phase HPLC with water/methanol mixtures as eluant, to give the title acid (0.14 g), mp 199°-200°.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:19][C:20]([C@H:22]1[O:24][C@@H:23]1[C:25]([O:27]CC)=[O:26])=[O:21])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+:32]>>[CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:19][C:20]([C@H:22]1[O:24][C@@H:23]1[C:25]([O-:27])=[O:26])=[O:21])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)[CH2:9][CH2:8]1)=[O:6].[Na+:32]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(c2ncccn2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)[O-])C(=O)N1CCN(c2ncccn2)CC1

Procedure:
In a manner similar to Example 9, ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2-pyrimidinyl)piperazine-1-yl carbonyl}-butylcarbamoyl]oxirane-2-carboxylate was hydrolyzed with sodium hydroxide to yield sodium (2S,3S)-3-[(s)-3-methyl-1-{4-(2-pyrimidinyl)piperazine-1-yl carbonyl}butylcarbamoyl]-oxirane-2-carboxylate.
Reaction SMILES: COC1C=C2C(=CC=1OC)C=CC(C([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:36])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:19][CH2:18]1)=O)C2.[H][H]>CO.[C].[Pd]>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([O:34][CH3:35])[C:27]=1[O:32][CH3:33])[C:23]([N:20]1[CH2:21][CH2:22][NH:17][CH2:18][CH2:19]1)=[O:36]
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)C=C2
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Yield: 147.6 %

Procedure:
In methanol (20 ml) is dissolved 1-(6,7-dimethoxy-3,4-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (0.6 g). The solution is subjected to catalytic reduction in a stream of hydrogen in the presence of a 10% palladium-carbon (0.3 g). The reaction mixture is filtered off. The filtrate is concentrated under reduced pressure. To the concentrate is added ether, and the mixture is stirred. The resulting colorless powder is collected by filtration to afford 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (0.5 g).
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[CH:3]=[C:4]4[CH2:9][CH2:8][CH2:7][CH2:6][N:5]4[N:1]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc2n(n1)CCCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCCC2
Yield: 56.3 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (0.166 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with flash-chromatography. Yield 56.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09 (d, 3H), 1.74-1.82 (m, 2H), 1.94-2.03 (m, 2H), 2.71-2.78 (m, 2H), 4.11 (t, 2H), 4.27 (dd, 1H), 4.36 (dd, 1H), 4.39-4.49 (m, 1H), 6.30 (s, 1H), 6.95 (d, 1H), 7.82 (d, 1H), 7.96-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.16 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(Cl)c1Cl
Product: COc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
To 5.31 g of 2,3-dichloroanisole is slowly added 10 ml of chlorosulfonic acid over a period of 30 minutes. The reaction is mildly exothermic and at the end of the addition, a clear solution is formed. The yellowish solution is stirred at room temperature for 1 additional hour and quenched with 200 g of crushed ice. The solid is filtered, air-dried and recrystallized from ether-pentane to give 6.9 g of 2,3-dichloro-4-methoxybenzenesulfonyl chloride as off-white prisms, mp 93°-95°.
Reaction SMILES: BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(C(C)(C)C)=CC=3)(=O)=O)C=2C=1.[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=[CH:48][C:42]=3[CH2:41][NH:40][C:39]=2[CH:53]=1.BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CNC=2C=1.[F:74][C:75]([F:88])([F:87])[O:76][C:77]1[CH:82]=[CH:81][C:80]([S:83](Cl)(=[O:85])=[O:84])=[CH:79][CH:78]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C>>[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:42]=3[CH2:41][N:40]([S:83]([C:80]3[CH:79]=[CH:78][C:77]([O:76][C:75]([F:74])([F:87])[F:88])=[CH:82][CH:81]=3)(=[O:85])=[O:84])[C:39]=2[CH:53]=1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(I)cc1NC2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21

Procedure:
The title compound was prepared following the procedure described for intermediate 53 substituting 8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 37) for 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine, and 4-(trifluoromethoxy)benzenesulfonyl chloride substituted for [(4-tert-butylphenyl)-sulfonyl chloride. LC/MS: m/e 615.8 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 7.80 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=7.8 Hz), 7.66 (1H, dd, J=8.5, 2.0 Hz), 7.55 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.2 Hz), 7.17 (1H, d, J=7.6 Hz), 7.15 (2H, d, J=8.6 Hz), 4.70-4.90 (2H, br).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:26](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:27][C:28]1([CH3:31])[CH2:30][CH2:29]1>>[CH3:31][C:28]1([O:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH:19]=3)[CH2:21][CH2:22]2)=[O:32])[CH2:30][CH2:29]1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Product: CC1(OC(=O)N2CCC(c3cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4o3)CC2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and 1-methyl-cyclopropyl 4-nitrophenyl carbonate following a procedure analogous to that described for Example 20. Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.C([O:18]O)(C)(C)C>ClCCl.CCCCCCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[O:18][CH:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: CC(C)(C)OO
Reactant: FC(F)(F)c1ccc2c(c1)CC=C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCCCCCC
Product: FC(F)(F)c1ccc2c(c1)CC1OC21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)-1H-indene (1.1 g, 6 mmol) in anhydrous dichloromethane (80 mL) at −78° C. was added a 5.5 M solution of tert-butyl hydroperoxide in n-decane (1.3 mL) followed by titanium tetrachloride (0.79 mL, 7.2 mmol). After being stirred at −78° C. for 1 h, the resulting brown solution was quenched with a mixture of Et2O/saturated Na2SO3 solution. The mixture was stirred at ambient temperature for 1 h to give a colorless solution. The organic layer was separated and washed with brine, dried over MgSO4 and concentrated to give the crude product (1.2 g) as a solid. LC/MS calculated for C10H7F3O: (M+H)+ 201; found 201.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([O:23]C)=[CH:7][CH:6]=1)=[O:4].[H][H]>CCO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:23])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2nc3c(C(=O)O)ccc(O)c3[nH]2)cc1
Yield: 100 %

Procedure:
2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (0.63 g, 1.92 mmol) obtained in step 2 was dissolved in 15 ml of EtOH, 0.1 g of 10% Pd/C was added thereto and stirred for 24 hours while hydrogen was supplied thereto from a balloon fulfilled with H2 gas. The resulting solution was filtered and dried to obtain the title compound (0.57 g, 1.92 mmol) in a yield of 100%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][NH:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[C:25]([O:34]N1C(=O)CCC1=O)([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=O>CC(C)=O.O>[CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:6][N:7]([CH3:8])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[O:34]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CC(C)(C)OC)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(C)(C)C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of the above (S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate (˜2.99 mmol) in acetone (9 mL) and water (3 mL), there was added K2CO3 (1.24 g, 9.0 mmol), followed by Teoc-OSu (0.85 g, 3.29 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum, and the aqueous residue was extracted with CH2Cl2 (4×5 mL). The combined organic layers were concentrated, and crude residue was purified with flash column chromatography to give (S)-tert-butyl 4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate (0.18 g, 15%, 3 steps) as a clear oil. 1H NMR (400 MHz, CDCl3): 4.82, 4.92 (br, 1H), 4.16 (m, 2H), 3.88 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 3.16 (s, 3H), 2.88, 2.90 (s, 3H), 1.44 (s, 9H), 1.18, 1.20 (s, 6H), 0.98 (m, 2H), 0.02 (s, 9H); MS m/z 405 (M+H+).