Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=2)=[O:12])[CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cc(Cl)ccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cc(Cl)ccc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 336 (125 mg, 0.21 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (90 mg, 73%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H)+]: 586.1471. found: 586.1473.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=1)=[O:38]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][N:9]([CH2:36][C:37](=[O:38])[NH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(CC(=O)Nc2ccc(Cl)cn2)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
(3R,4R)-4-[2-Fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride (0.315 g; synthesis described in EP04101265.9 example 28 step 3) is suspended in acetonitrile (10 ml) and K2CO3 (0.425 g) is added as solid. 2-Bromo-N-(5-chloro-2-pyridinyl)-acetamide (0.23 g) is added and the reaction mixture is stirred at 25° C. for 18 h. After that the mixture is heated for 3 h to 80° C., cooled to 25° C. and filtered. The filtrate is evaporated to dryness followed by flash chromatography over silica gel using DCM/MeOH/NH3 as eluent to yield 0.203 g (46.3%) (3R,4R)-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarba-moyl]-pyrrolidine-3-carboxylic acid ethyl ester. White solid. MS 542.3 [M+H+].
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1N(c1ccccc1)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (7.8 mL) in methylene chloride (125 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(2-methoxy-phenyl) aniline, prepared as in Part A, (14.51 g, 87.9 mmol) in methylene chloride (125 mL) and triethylamine (12.3 mL) and the resultant mixture is allowed to attain RT overnight. After 18 h an additional 2.0 mL of bromoacetyl bromide is added and the resultant reaction mixture stirred at RT for 4 h. The reaction mixture is washed with 1N hydrochloric acid (3×100 mL), water (2×100 mL), brine (100 mL), dried, (MgSO4) and concentrated in vacuo to afford N-Isopropyl-N-(2-methoxy-phenyl) bromoacetamide(20.3 g) as a dark mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ7.45 (dt, 1H, J=7.8, 1.4), 7.20 (dd, 1H, J=7.8, 1.4), 7.04 (m, 2H), 4.90 (m, 1H, J=6.8), 3.85 (s, 3H), 3.60 (dd, 2H, J=32.9, 11.5), 1.20 (d, 3H, J=6.8), 0.97 (d, 3H, J=6.8).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:12](/[CH:14]=[C:15](/[O-])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:13].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:13][C:12]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])[N:6]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1
Reactant: NNCc1cccc(F)c1F
Reactant: CCOC(=O)/C([O-])=C\C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(Cc2cccc(F)c2F)n1

Procedure:
Preparation takes place in analogy to that described in Example 7 A from 1.50 g (9.48 mmol) of 1-(2,3-difluorobenzyl)hydrazine from Example 2 A, 1.55 g (9.48 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A, 1.73 g (1.17 ml; 15.18 mmol) of trifluoroacetic acid and 40 ml of dioxane.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=1[CH:30]=O.[Cl-].[NH4+]>O1CCCC1>[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=1/[CH:30]=[CH:12]/[C:11]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:13]
Reactant: Cc1cccc(C)c1C=O
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1/C=C/C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Under argon atmosphere, 1M tetrahydrofuran solution of 1.3 ml of lithium bis(trimethylsilyl)amide was added at −78° C. to a solution of 300 mg of tert-butyl 4-acetylpiperidine-1-carboxylate in 4.0 ml of tetrahydrofuran, followed by stirring for 15 minutes. To the reaction mixture, a solution of 167 mg of 2,6-dimethylbenzaldehyde in 1.0 ml of tetrahydrofuran was added, followed by stirring at ambient temperature for 12 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 235 mg of tert-butyl 4-[(E)-3-(2,6-dimethylphenyl)prop-2-enoyl]piperidine-1-carboxylate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CCOC(C)=O>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Cc2ccccc2)CC1
Yield: 97.1 %

Procedure:
Acylation of N-Boc-piperazine (1.86 g, 10 mmoL) with benzylsulfonyl chloride (1.9 g, 10 mmol) in CH3CN (20 mL) in the presence of Na2CO3 (1.01 g, 12 mmol) was carried out at rt for 16 hours. The mixture was diluted with EtOAc (150 mL), washed with water (50 mL), dried over MgSO4, and concentrated to give 1N-Boc-4N-benzylsulfonyl-piperazine (3.3 g, 98%). 1H NMR (CDCl3) δ 7.39 (bs, 5H), 4.23 (s, 2H), 3.38-3.35 (m, 4H), 3.07-3.05 (m, 4H), 1.44 (s, 9H). The Boc-intermediate was deprotected with 4M HCl in dioxane (20 mL) at rt for 1 hour. The mixture was diluted with EtOAc, washed with 1N NaOH and water, dried over MgSO4, and concentrated to give the product (1.9 g, 81%). 1H NMR (CDCl3) δ 7.46-7.43 (bs, 5H), 4.22 (s, 2H), 3.11-3.08 (m, 4H), 2.83-2.79 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27]C=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[O:31]1[C:35]2([CH2:40][CH2:39][CH2:38][CH:37](S)[CH2:36]2)[O:34][CH2:33][CH2:32]1>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[O:31]1[C:35]2([CH2:40][CH2:39][CH2:38][CH:37]([S:3]([C:2]3[CH:27]=[CH:28][C:23]([S+:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]4[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=4)=[CH:24][CH:25]=3)(=[O:6])=[O:4])[CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: SC1CCCC2(C1)OCCO2
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccc([S+](c2ccccc2)c2ccccc2)cc1)C1CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 132.3 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution and 11.8 g of 1,4-dioxaspiro[4.5]decane-7-thiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was further shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 25.3 g of [4-(1,4-dioxaspiro[4.5]decan-7-ylsulfonyl)phenyl]diphenylsulfonium trifluoromethanesulfonate.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[C@@H:11]([O:20][CH2:21][O:22][CH3:23])[CH2:10]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:23][O:22][CH2:21][O:20][C@H:11]1[C@H:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH2:13][C@H:9]([OH:8])[CH2:10]1
Reactant: COCO[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1c1ccnn1C
Agent: [Pd]
Solvent: CCO
Product: COCO[C@@H]1C[C@@H](O)C[C@H]1c1ccnn1C
Yield: 83.9 %

Procedure:
A solution of the 5-[(1R*,2S*,4S*)-4-(benzyloxy)-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole (250 mg, 0.790 mmol) prepared in Example 106a and palladium carbon (5%; 200 mg) in ethanol (3.0 mL) was stirred for 5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=96:4) to yield the title compound (150 mg, 84%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:23]3[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: O=C1Nc2cc(F)ccc2Oc2ccccc21
Product: CCN1CCN(C2=Nc3cc(F)ccc3Oc3ccccc32)CC1

Procedure:
Prepared in the same manner as Example 1 starting with 8-fluoro-10H-dibenzo[b,f][1,4]oxazepin-11-one (2, X=O, R1=F) with 1-ethyl piperazine. This compound was an oil with 1H NMR (400 MHz, CDCl3), 1.16 (t, 3H, J=7.2 Hz, CH3), 2.55 (q, 2H, J=7.2 Hz, —CH2—), 2.55-2.65 (broad s, 4H, piperazinyl CH2) 3.55-3.65 (broad s, 4H, piperazinyl CH2), 6.64 (ddd, 1H, J=2.4, 6.6 and 7.2 Hz), 6.82 (dd, 1H, J=2.1 and 7.5 Hz), 7.12 (dd, 1H, J=4.2 and 6.2 Hz), 7.21 (doublet of triplets, 1H, J=0.8 and 6.0 Hz), 7.23 (dd, 1H, J=0.9 and 6.3 Hz), 7.34 (dd, 1H, J=1.2 and 5.7 Hz), 7.44 (doublet of triplets, 1H, J=1.2 and 6.0 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10](=[CH2:13])[CH:9](O)[CH2:8]1)=[O:6])[CH3:3].S(Cl)([Cl:18])=O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:13][Cl:18])=[CH:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(CCl)CC1
Temperature: 60 °C
Yield: 76.4 %

Procedure:
The intermediate obtained from Step A (400 mg, 1.88 mmole) was dissolved in 10 mL benzene and thionyl chloride (165 ml, 2.26 mmole) was added and heated to 60° C. for 25 minutes. The resulting mixture was poured into NaHCO3 (aq.) and extracted with ether. The ether layer was dried over magnesium sulfate and concentrated to give title compound (333 mg, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH3:10])=[O:8].CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].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>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:3][CH:2]([CH3:1])[CH3:22]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(CC(C)C)c1
Reactant: COc1ccc(F)c(B(O)O)c1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CC(C)C)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 77.2 %

Procedure:
To a stirred solution of 66.20D (0.400 g, 1.2 mmol) in DMF (4.00 mL, 52 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.40 g, 2.4 mmol) (commercially available from Aldrich), potassium carbonate (0.49 g, 3.5 mmol), and then tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol). The mixture was heated to 90° C. and stirred for 22 hours. The mixture was cooled to room temperature, diluted with brine, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.20E as a colorless oil (0.293 g, 79% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[C:3]2=[CH:15][N:14]([CH3:16])[N:13]=[C:4]12)[CH3:18]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nn(C)cc2c1=O

Procedure:
22.1 g. of 4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.1 mol.), 17.1 g. of ethyl iodide and 21 g. of potassium carbonate (0.15 mol.) are stirred together in 200 ml. of dimethylformamide at 80° for 12 hours. The inorganic precipitate is filtered off and the filtrate evaporated to dryness. Recrystallization of the residue with ethyl acetate yields 18.2 g. of 7-ethyl-4,7-dihydro-2-methyl-4-oxo-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, yield (73%); m.p. 170°-172°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:61])[N:40]([CH2:44][CH:45]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[C:46]1[CH:47]=[N:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[CH2:41][CH2:42][OH:43])([CH3:37])([CH3:36])[CH3:35].[N+:62]([C:65]1[CH:70]=[CH:69][C:68](O)=[CH:67][CH:66]=1)([O-:64])=[O:63]>C1COCC1>[C:34]([O:38][C:39](=[O:61])[N:40]([CH2:44][CH:45]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[C:46]1[CH:47]=[N:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[CH2:41][CH2:42][O:43][C:68]1[CH:69]=[CH:70][C:65]([N+:62]([O-:64])=[O:63])=[CH:66][CH:67]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1)CC(O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
To a cooled (0° C.), stirred solution of triphenylphosphine (629 mg) in THF (6 mL) was added diisopropylazodicarboxylate (0.5 mL) dropwise and the resulting thick white slurry was stirred for 45 min. A solution of [2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (515 mg) and 4-nitrophenol (332 mg) in THF (5 mL) was added dropwise to produce a yellow slurry. After an additional 1 h period, the cooling bath was removed and the mixture was allowed to stir at ambient temperature for 20 h. This mixture was concentrated in vacuo and chromatographed on a Biotage® F40M column (gradient of 10% to 15% ethyl acetate/hexanes) to afford 530 mg of the title compound (I-3c) as a colorless foam.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.[O:21]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36]=2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:31][CH:30]=1)[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CCOCC.CCOCC.C1COCC1>[O:21]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]([OH:44])([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)[C:36]=2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:33][CH:34]=1)[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1(O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 113.8 %

Procedure:
To dry magnesium turnings (119 mg, 4.9 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (0.61 ml, 4.9 mmol) in 9: 1 Et2O/THF (10 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxylate (1.00 g, 2.5 mmol) in Et2O (60 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 5 min. The mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide the title compound (1.47 g) which was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.CC1C=CC=C(C)C=1C1C=CC(C([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=O)=CC=1>N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=[O:21])=[CH:17][CH:18]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CSc1ccccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To 20 mL of thionyl chloride was added 0.244 g (0.001 mol) of 2′-(methylthio)-1,1′-biphenyl-4-carboxylic acid of Step A. The solution was heated under reflux for 1 hour. The excess thionyl chloride was removed in a vacuo. To the residue was added 25 mL of dry pyridine and 0.318 g (0.001 mol) of N-(pyridyl-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12. The reaction was allowed to stand at room temperature for 1 hour and the pyridine was removed in vacuo. The residue was collected and washed with water giving a tan solid (0.62 g), m.p. 172-175° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:4]1.CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[N:4]=1)=[O:9]
Reactant: COC(=O)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
A suspension of 60% dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0° C., and methyl 3-pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0° C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidine-carboxylate (1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N-dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60° C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated in vacuo, and purified by medium-pressure liquid chromatography on silica gel eluting with 0-10% methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:17]([CH3:19])[CH3:18])[C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][OH:7]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:17]([CH3:19])[CH3:18])[C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:6]=[O:7]
Reactant: CN(C)c1cc(CO)cc(N(C)C)c1N1CCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(C)c1cc(C=O)cc(N(C)C)c1N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12.9 G. of 3,5-bis(dimethylamino)-4-piperidinobenzyl alcohol, 17.1 g. of activated manganese dioxide and 80 ml. of chloroform were mixed together and stirred at room temperature for 48 hours. The manganese dioxide was filtered off, washed with chloroform and the chloroform evaporated. After purification over aluminum oxide with benzene and recrystallization from ethanol, there was obtained 3,5-bis(dimethylamino)-4-piperidinobenzaldehyde having a melting point of 114°-116° C.