Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N1CCN(C2C=C(N[C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[N:43][CH:42]=4)=[CH:39][CH:40]=3)=[O:30])C=CC=2)CC1)C>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[C:38]([C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[N:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Product: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3cncc4ccccc34)c3nccnc23)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-isoquinolin-4-yl-quinoxaline-5-car-boxylic acid (Example 52). Title compound: ESI-MS: 464.1 [M+H]+; tR=8.23 min (System 2).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(CC1CCOCC1)NO
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(CC3CCOCC3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-(tetrahydro-pyran-4-yl)-acetamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.13 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCCCC1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)COc1ccc(CC2=C(C)C(=O)C(OC)=C(OC)C2=O)cc1C(=O)N1CCCCC1
Yield: 73.5 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(methoxycarbonylmethyloxy)benzoyl]piperidine (0.260 g, 0.520 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.713 g, 1.30 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:3) to obtain the titled compound (0.180 g, 0.382 mmol, 73%).
Reaction SMILES: Cl.[C:2]([CH2:4][C@@H:5]1[CH2:13][C@@H:12]2[C@@H:8]([CH2:9][NH:10][CH2:11]2)[C@@:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])([OH:14])[CH2:6]1)#[N:3].ClCCl.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](O)=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C)CCCN=C=NCC>O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>[C:2]([CH2:4][C@@H:5]1[CH2:13][C@@H:12]2[C@@H:8]([CH2:9][N:10]([C:41](=[O:42])[CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)[C@@:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])([OH:14])[CH2:6]1)#[N:3]
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CN(C(=O)Cc3ccccc3OCc3ccccc3)C[C@H]21
Yield: 55 %

Procedure:
The procedure is as described in Example 4, starting from 1.61 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride, 50 cm3 of dichloromethane, 0.70 cm3 of triethylamine, 1.21 g of (2-benzyloxyphenyl) acetic acid, 0.02 g of hydroxybenzotriazole hydrate and 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Purification by chromatography followed by recrystallization from ethyl acetate give 1.4 g of (3aS,4S,6S,7aR)-6-cyanomethyl-2-[(2-benzyloxyphenyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol are obtained in the form of white crystals.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:20](=O)(SC)OC(OC(=O)C(C)(C)C)C>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[C:2]([CH3:20])([CH3:4])[CH3:3]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: CSC(=O)OC(C)OC(=O)C(C)(C)C
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)(C)C

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (5) affords [(1-pivaloyloxyethoxy)carbonyloxy]succinimide (19).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1>CCOCC.CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccn1Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)c2cccn2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.8 %

Procedure:
The following was added sequentially to anhydrous DMF (6 mL): 1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylic acid (175 mg, 0.743 mmol), Hunig's Base (389 μl, 2.228 mmol), EDC (157 mg, 0.817 mmol), HOBT (125 mg, 0.817 mmol), and finally ethyl piperidine-4-carboxylate (172 μl, 1.114 mmol). The reaction was allowed to stir at room temperature for 24 h. At this time, a 1:1 solution of EtOAc:Et2O (100 mL) was added and washed with 10% Na2CO3 (2×50 mL) and brine (1×50 mL). The organic solution was then dried with anhydrous MgSO4 and concentrated in vacuo. Material was purified by column chromatography (20 g silica, 20% EtOAc/Hexanes) to provide 211 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15]3=[C:16]([C:18](=[O:21])[CH:19]=[CH:20][N:14]3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:17]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C(Cl)Cl>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:15]3=[C:16]([C:18](=[O:21])[CH:19]=[CH:20][N:14]3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:17]=1
Reactant: COC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=c1ccn2c3ccccc3c3cc(CO)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-methoxycarbonyl-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) produced in Example 176 was suspended in anhydrous methylene chloride (100 ml), and diisobutylaluminium hydride (1M solution in methylene chloride, 4.3 ml) was added dropwise to the suspension in an acetone-dry ice bath. The mixture was stirred at room temperature for 1 hour, and methanol and water was added to the reaction mixture. The floating materials formed were separated by filtration, and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (70 mg, 26%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH3:14])[C:9]1=[S:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:27][N+:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][C:29]=1SC>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:29]2[N:28]([CH3:27])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30]2)[N:10]([CH3:14])[C:9]1=[S:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(=O)N(Cc2ccccc2)C1=S
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CN1C(=S)N(Cc2ccccc2)C(=O)C1=C1Sc2ccccc2N1C
Yield: 85.3 %

Procedure:
To a mixture of intermediate 3-benzyl-1-methyl-2-thioxoimidazolidin-4-one (0.33 g, 1.5 mmol) and 3-methyl-2-methylthiobenzothiazol-3-ium p-toluenesulfonate 0.66 g, 1.8 mmol) in anhydrous MeCN (10 mL) added dropwise TEA (0.28 mL, 2.0 mmol). After 2 h the resulting product mixture was concentrated and chromatographed (silica gel, DCM) to afford the title compound (0.47 g, 85%) as an orange-yellow solid. 1H-NMR (CDCl3): δ 7.54-7.61 (3H, m), 7.46 (1H, m), 7.21-7.33 (5H, m), 5.19 (2H; s), 3.86 (3H, s), 3.77 (3H, s).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]([CH3:26])[CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:19]([CH2:18][C@H:17]([N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H](CNc1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Solvent: ClCCl
Product: C[C@H](CN(C(=O)c1ccc(C#N)cc1)c1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of {(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-pyridin-2-ylamine (0.846 g, 2.38 mmol) in dichloromethane (20 mL) was treated at 0° C. with the dropwise addition of a dichloromethane solution of 4-cyanobenzoyl chloride (1.1 equivalents, 2.63 mmol in 5 mL). After stirring for 16 hours the mixture was poured onto hexane (100 mL) to precipitate the titled compound as its mono-hydrochloride salt (white solid, 1.2 g, 97% yield), which was recrystallized from dichloromethane/hexane.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[O:20])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=O.[BH4-].[Na+]>CO>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:19](=[O:20])[NH:18][C:16]1[CH:15]=[N:14][N:13]([CH2:12][C:9]2[O:8][C:7]([CH2:5][OH:4])=[CH:11][CH:10]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cnn(Cc2ccc(CO)o2)c1)OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-[4-(2-chloro-benzyloxycarbonylamino)-pyrazol-1-ylmethyl]-furan-2-carboxylic acid methyl ester (3.30 g, 8.46 mmol) in MeOH (33.0 mL) was treated portionwise, at rt with NaBH4 (3.33 g, 84.60 mmol). The reaction mixture was stirred at rt overnight before being quenched by pouring in sat. aq. NH4Cl (100 mL), extracted with EA (3×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (30:70 hept-EA) gave the title compound. TLC: rf (30:70 hept-EA)=0.22. LC-MS-conditions 02: tR=0.86 min; [M+H]+=362.32. 1H NMR (400 MHz, CDCl3) δ 2.94 (s, 1H), 4.52 (s, 2H), 5.15 (s, 2H), 5.28 (s, 2H), 6.21 (s, 1H), 6.28 (s, 1H), 7.04 (s, 1H), 7.22-7.35 (m, 2H), 7.35 (s, 1H), 7.35-7.46 (m, 2H), 7.69 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=[CH:5][C:4]=1[F:25])#[N:2].CC[OH:28]>CS(C)=O.[OH-].[Na+].OO>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[CH:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:28])=[C:4]([F:25])[CH:5]=1)[CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: CCO
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(4-cyano-3-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (38 mg, 0.105 mmol) in EtOH (1 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.4 mL) and H2O2 (50% aq., 0.4 mL) were added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was acidified with HOAc (0.5 mL), and then was purified by HPLC to give the titled compound (18 mg). MS 380.3 (M+H); UV 221.1, 282.9, 297.7 nm
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])([CH3:11])[CH3:10]>>[CH3:8][Si:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:11])[CH3:10]
Reactant: CC(=O)C(=O)Cl
Reactant: C[C@H](N)C(=O)O[Si](C)(C)C
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](C)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-alanine or pyruvyl-glycine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting pyruvyl chloride with a suspension of alanine trimethylsilyl ester hydrochloride to yield a pyruvyl-alanine trimethylsilyl ester and then subjecting the pyruvyl-alanine trimethylsilyl ester to hydrolysis to yield pyruvyl-alanine. The pyruvyl-alanine synthesized via the method set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+]>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([OH:18])=[O:17])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (3.17 g) in ethanol (40 mL) was added 10% potassium hydroxide (2.42 g). The mixture was stirred at room temperature for 5 hours and evaporated. Water was added to the residue and pH was adjusted to 7. White precipitates of the title compound were collected by filtration and the compound was used for next step without further purification.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21](C5C=C(C6C=CC=CC=6CCC=C)C=CC=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:39])[C:15]=3[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[CH2:51][CH2:52]Cl>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:46]([O:45][C@@H:40]([C:15]1[C:16]([CH3:39])=[N:17][C:18]2=[CH:22][C:21]3=[N:20][N:19]2[C:14]=1[C:11]1[CH:12]=[C:13]2[C:8]([O:7][CH2:6][CH2:5][CH:4]2[CH2:1][CH:2]=[CH:3][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=2[C:52]2[CH:51]=[C:3]3[CH:2]=[CH:1][CH:4]=2)=[CH:9][CH:10]=1)[C:41]([O:43][CH3:44])=[O:42])([CH3:49])([CH3:47])[CH3:48]
Reactant: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4)C(CC=C)CCO5)n3n2)c1
Reactant: ClCCCl
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1ccc2c(c1)C(CC=CCCc1ccccc1-c1cccc-3c1)CCO2
Reaction time: 1.5 h

Procedure:
A solution of (2S)-methyl 2-(7-(4-allylchroman-6-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.054 g, 0.082 mmol) in DCE (5.0 mL) was heated (70° C.), then treated with Hoveyda-Grubbs Cat. 2nd Gen. (5 mg, 8 μmol). The reaction was stirred for 90 min. The reaction was cooled, then concentrated and the residue was used immediately in the following step. LCMS (M+H)=628.4.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[N:41]1([CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31]([NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: C1COCCN1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CN3CCOCC3)cc1)C2

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and morpholine in the manner of Example 42, m.p. 191-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])[CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: COc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCCC2)c1
Yield: 126.2 %

Procedure:
A solution of 3-methoxybenzoic acid (13.5 g, 88.8 mmol), pyrrolidine (9 mL, 133 mmol), HATU (33 g, 88.8 mmol) and DIEA (30 mL, 172 mmol) in DMF (100 mL) was stirred at room temperature for 2 h. The solution was added water and extracted with ethyl acetate (200 mL×3). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography (eluted with petroleum ether:ethyl acetate=2:1 to 1:1) to give (3-methoxyphenyl)(pyrrolidin-1-yl)methanone (23 g, 100%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (250 mg) obtained in Step D of Example 12 in methanol (20 mL) was added 1N aqueous sodium hydroxide solution (4 mL) under ice-cooling, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure to evaporate the methanol, and the mixture was partitioned between ethyl acetate and 1N hydrochloric acid (8 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (238 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:22][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 159.8 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 28.9 g (0.2 mol, 2.0 eq.) of 1-nonanol were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 160 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8.5 g). Subsequently, the resultant was extracted with 160 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to obtain 42.4 g of 4-nonyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [C:1](=[S:19])([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)[NH2:2].Cl[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[C:15]([C:6]1[CH:5]=[C:4]([O:3][C:1]2[S:19][CH:21]=[C:22]([CH3:23])[N:2]=2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(OC(N)=S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCl
Solvent: O
Solvent: CC(=O)O
Product: Cc1csc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 58.7 %

Procedure:
O-(3,5-Di-tert-butyl-4-hydroxyphenyl) thiocarbamate (1.5 g) and 1.3 g of chloroacetone were dissolved in 60 ml of acetic acid, and the solution was heated at 90°-100° C. for 15 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:4) to give 1.0 g of the desired compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:31]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].CN(C=O)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:36]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1coc(Oc2cccc(C(C)(C)C)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 182.4 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.10 mmol), K2CO3(17 mg, 0.12 mmol), 3-tert-butyl phenol (18 mg, 0.12 mmol), DMF (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 130° C. for 10 min. The reaction mixture was diluted with EtOAc, and washed with saturated ammonium chloride and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (90 mg, 80%).