Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[CH3:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.13 h

Procedure:
A mixture of 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (7.0 mg, 0.019 mmol, from Example 206) and acetaldehyde (5.2 μL, 0.093 mmol, Aldrich) in DCM (2.4 mL) was treated with Na(OAc)3BH (5.2 mg, 0.024 mmol, Aldrich). After 8 minutes, the solvent was removed in vacuo, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (2.0 mg, 26%).
Reaction SMILES: [NH3:1].[CH3:2][O:3][CH:4]([O:9][CH3:10])[CH2:5][N:6]=[C:7]=[S:8]>CO>[CH3:2][O:3][CH:4]([O:9][CH3:10])[CH2:5][NH:6][C:7]([NH2:1])=[S:8]
Reactant: COC(CN=C=S)OC
Reactant: N
Solvent: CO
Product: COC(CNC(N)=S)OC

Procedure:
Methanol (200 mL) was saturated with ammonia and stirred with isothiocyanatoacetaldehyde dimethyl acetal (5.0 g) for 2 h. The mixture was concentrated and the residue was chromatographed (silica gel, 5% methanol/dichloromethane) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cccc(Br)c1
Yield: 67.2 %

Procedure:
A solution of (3-(3-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmoles), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 mg, 1.34 mmoles) at room temperature for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (293 mg, 67%).
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC1CN(C(C)(C)C)CC2(CCNCC2)O1
Reaction time: 0.25 h
Yield: 104 %

Procedure:
Tert-butyl 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (530 mg, 1.56 mmol) was dissolved in dichloromethane and treated with a solution of HCl in dioxane (8.0 mL of 4 M, 33 mmol) and stirred for 15 min. The reaction mixture was diluted with dichloromethane and washed with 1:1 saturated NaHCO3/1 M NaOH. The organic layer was dried over Na2SO4, filtered and concentrated to provide 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 99%) as an oily solid. ESI-MS m/z calc. 240.2. Found 241.3 (M+1)+; Retention time: 0.21 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][N:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].Cl.[CH3:36][O:37][NH2:38].N#N>CCO>[CH3:36][O:37]/[N:38]=[CH:24]/[C:23]1[CH:26]=[CH:27][C:20]([O:19][C:16]2[CH:17]=[N:18][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: CON
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Agent: Cl
Agent: N#N
Solvent: CCO
Product: CO/N=C/c1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 6-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)oxy)nicotinaldehyde (101) (60 mg, 0.126 mmol) in dry EtOH (1.265 mL) was added O-Methylhydroxylamine hydrochloride (21.13 mg, 0.253 mmol) in a 5 mL vial under N2 atmosphere. The reaction mixture was stirred at RT overnight. The reaction mixture was evaporated and the crude residue was purified on silica (ISCO, 12 gram column, gradient to 75% EtOAc/Hexanes over 25 minutes) to afford the title compound. Yield=18 mg (26.9%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.3 Hz, 1H), 8.11 (dd, J=8.7, 2.4 Hz, 1H), 8.04 (s, 1H), 7.67 (dd, J=8.7, 2.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.36 (td, J=8.8, 6.4 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.83-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.63 (d, J=14.3 Hz, 1H), 5.10 (d, J=14.3 Hz, 1H), 3.99 (s, 3H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ−103.20 (d, J=17.7 Hz), −103.89 (ddd, J=31.3, 21.1, 13.6 Hz), −108.11 (d, J=9.5 Hz), −110.21 (d, J=45.0 Hz), −110.90 (d, J=45.0 Hz). MS (ESI): m/z 504.2 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:9]=1[O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:9]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH2:1])[C:8]=1[NH2:7])([O-:26])=[O:25]
Reactant: CC(C)(C)[O-]
Reactant: Nc1c(OCC(=O)c2ccccn2)cccc1[N+](=O)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(COc1cccc([N+](=O)[O-])c1N)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Potassium tert-butoxide (1.10 g, 9.9 mmol) was added to a suspension of methyl triphenylphosphonium bromide (3.0 g, 8 mmol) in tetrahydrofuran (30 mL) under nitrogen. The reaction was stirred at room temperature for 1 h, followed by addition of 2-(2-amino-3-nitrophenoxy)-1-pyridin-2-ylethanone (2 g, 8 mmol). The mixture was stirred for 3 h, and was then partitioned between water and ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 2-nitro-6-[(2-pyridin-2-ylprop-2-en-1-yl)oxy]aniline as light brown solid (0.5 g, 20%). LCMS calculated for C14H14N3O3 (M+H)+: m/z=272.1. found: 272.1.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([O:19][C:20]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:25][CH:26]=1)=[O:28])[CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CCCCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCCCOC(=O)c1ccc(Nc2ncc(C(=O)OCC)c(=O)[nH]2)cc1
Reaction time: 48 h
Yield: 41.7 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and butyl -4-aminobenzoate (10.8 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(4-butoxycarbonylanilino)-6-oxo-5-pyrimidinecarboxylate (7.0 g). M.p. 281°-283° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[Cl-].[CH2:31]([O:33][C:34](=[O:40])/[CH:35]=[CH:36]/[C:37](O)=[O:38])[CH3:32]>C(O)C>[C:34]([O:33][CH2:31][CH3:32])(=[O:40])/[CH:35]=[CH:36]/[C:37]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: [Cl-]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C/C(=O)OCC
Reaction time: 2 h

Procedure:
135 g (0.5 mole) of 1-octadecanol and 65 ml (0.55 mole) of quinoline are dissolved, with stirring, at 40° C. in 500ml of ethanol-free chloroform. Over the course of one hour, 89.4 g (0.55 mole) of fumaric acid monoethylesterchloride were added drop by drop to the clear solution and it was boiled for 2 hours under reflux. The reaction mixture was diluted with 500 ml of petroleum ether and extracted twice with 0.5N hydrochloric acid, water, 5% potassium carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was recrystallized from 95% ethanol. Yield: 139 g of product having a melting point of 42° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]2=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[C:5]2=[CH:4][CH:3]=1
Reactant: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCCO)c2cnccc2n1C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21

Procedure:
To the alcohol 14 (5 g, 12.11 mmoles) dissolved in DCM (80 mL) was added dess-martin periodinane (6.934 g, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at Rt overnight. Diethylether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtrated and the filtrate washed quickly with an aqueous Na2S2O3 solution, dried on Na2SO4, filtrated and evaporated. The resulting solid was washed again with a solution of 5% methanol in dichloromethane and the filtrate was washed with a Na2S2O3 solution and dried over Na2SO4. The solution was concentrated and the aldehyde 67-1 was obtained as a light yellow solid (4.6 g, 93% yield) and was used as such in the next step. LCMS m/z=411 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([O:18][S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C1CCN(C)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(OS(=O)(=O)c3ccccc3)cc2c1C1CCN(C)CC1
Yield: 24.2 %

Procedure:
By a method similar to Example 31, using 2-methyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (250 mg, 1.03 mmol), benzenesulfonyl chloride (0.22 g, 1.25 mmol), 0.2N sodium hydroxide and THF (2 mL) gave 96 mg (24%) of the title compound: mass spectrum (ES+)=385.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:35][C:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:42]5[CH:41]=[CH:40][CH:39]=[C:38]([C:36](=[O:37])[NH2:35])[CH:43]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(N)=O)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-aminocarbonyl-phenylboronic acid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])=[O:14]>O1CCCC1>[CH3:8][O:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH:18]=[O:19])=[O:14]
Reactant: O=Cc1cccc(C(=O)Cl)c1
Reactant: COCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 16.70 g of triethylamine and 12.40 g of 2-methoxyethylamine was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at room temperature. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 10.79 g of oily 3-[(2-methoxyethyl)aminocarbonyl]benzaldehyde [Compound No. (d)].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: COC(=O)/C=C/C(=O)c1ccco1
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(c2ccco2)OC(=O)[C@H]1Cc1ccccc1
Yield: 94 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-furanylbut-2-enoate using 0.5 mol % 1 as the catalyst in 94% yield as an 8:1 mixture of diastereomers (brown oil). [α]D20 (c 1.03, CHCl3)=+119.5; 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 4H), 7.18-7.16 (m, 2H), 6.67 (d, 1H, J=3.4 Hz), 6.47* (dd, 1H, J=3.2, 2.0 Hz), 6.45 (dd, 1H, J=3.2, 1.6 Hz), 5.74 (d, 1H, J=7.0 Hz), 5.70* (d, 1H, J=6.0 Hz), 3.77 (s, 3H), 3.68* (s, 3H), 3.55 (dd, 1H, J=14.3, 4.7 Hz), 3.52-3.46* (m, 1H), 3.40-3.35* (m. 1H), 3.29-3.26 (m, 1H), 3.15* (dd, 1H, J=13.6, 5.6 Hz), 3.03-2.97 (m, 1H), 2.90* (dd, 1H, J=13.6, 10.0 Hz), 2.74 (dd, 1H, J=14.3, 10.1 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 168.4, 146.5, 145.3, 143.7, 138.0, 131.6, 129.6, 129.4, 128.9, 128.8, 127.4, 127.1, 111.8, 109.0, 108.9, 96.4, 94.0, 53.6, 52.9, 52.8, 43.0, 42.6, 40.8, 40.2, 35.5, 33.4; IR (thin film) ν 3063, 3029, 2953, 1781, 1734, 1495, 1455, 1264, 1225, 1201, 1174, 1085, 1009 cm−1; HRMS (ESI) calcd for C18H16O5 [M+Na]+ 335.0889, found 335.0890; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 20:1 hexanes/i-PrOH), tr (3S,4S)=31.9 min, tr (3R,4R)=22.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:27][C:28]1[CH:32]=[CH:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)[N:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([N:30]4[CH:31]=[CH:32][C:28]([CH3:27])=[N:29]4)=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Product: COC(=O)C1CN(C(=O)c2ccc(-n3ccc(C)n3)cc2Cl)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-1-pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white solid. Anal. for C29H27ClN4O6S: Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C, 58.2; H, 4.9; N, 8.9.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:20](=[O:22])[CH3:21])=[CH:13][CH:12]=2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Into the solution of 4-((Perfluoropyridin-4-yl)ethynyl)aniline, (13a) (0.158 g, 0.59 mmol) in 3 mL of CH2Cl2 were added acetic anhydride (0.134 g, 1.26 mmol) and Et3N (0.128 g, 1.26 mmol). The reaction mixture was stirred at room temperature overnight. After concentrating the solution in vacuo, the product was isolated by column chromatography (EtOAc:Hexane=1:2 to 1:1) with 85% yield: 1H-NMR (400 MHz, CD3OD) δ 7.70 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 2.15 (s, 3H); 13C-NMR (150 MHz, CD3CN) δ 170.1, 144.5 (dm, J=237 Hz), 143.1 (dm, J=259 Hz), 142.7, 134.2, 120.0, 115.4, 107.5 (t, J=3.4 Hz), 73.6 (t, J=4.3 Hz), 24.5; HRMS (ESI+): calcd for C15H9F4N2O1 [M+H]+ 309.06510, found 309.06678; m.p. 189-190° C.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].[CH3:16]O>>[N+:5]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])([O-:7])=[O:6]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1[nH]ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Thionyl chloride (9.2 mL) was added dropwise to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (19.77 g, 125.9 mmol) in methanol (200 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give methyl 4-nitro-1H-pyrazole-5-carboxylate (17.8 g, 82%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1C=C(C(C2C=C(C)C3NC(=O)OC=3C=2)=O)C(C)=CN=1.[Cl:24][C:25]1[C:30]([CH3:31])=[C:29]([C:32]([C:34]2[CH:43]=[C:42]([CH3:44])[C:37]3[NH:38][C:39](=[O:41])[O:40][C:36]=3[CH:35]=2)=[O:33])[CH:28]=[CH:27][N:26]=1.IC>CN(C=O)C>[Cl:24][C:25]1[C:30]([CH3:31])=[C:29]([C:32]([C:34]2[CH:43]=[C:42]([CH3:44])[C:37]3[N:38]([CH3:4])[C:39](=[O:41])[O:40][C:36]=3[CH:35]=2)=[O:33])[CH:28]=[CH:27][N:26]=1
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Reactant: Cc1c(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)ccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)ccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.10 g (2.2 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.61 g (2.0 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF at RT. The reaction mixture was stirred for 30 min at RT. Then 0.17 mL (2.6 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then a further 0.1 mL iodomethane were added and the mixture was stirred further at RT. Ice water was added to the reaction mixture and the precipitate formed was suction filtered. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down, triturated with diethyl ether, suction filtered and dried. The product was obtained in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and reacted further as such.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[C:9]([OH:12])=[N:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:7]=1
Reactant: BrBr
Reactant: CCS(=O)(=O)c1ccc(O)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution crude of 5-ethanesulfonyl-pyridin-2-ol prepared above, and sodium acetate (3.74 g, 45.6 mmol) in acetic acid (50 mL) was added a solution of bromine (7.3 g, 46.0 mmol) in acetic acid (10 mL) dropwise over a period of 1 hour. After being stirred at room temperature overnight, additional bromine (7.3 g, 46.0 mmol) in acetic acid (10 mL) was added dropwise to the reaction mixture over a period of 1 hour. After being stirred overnight, the reaction mixture was warmed to 30° C. and stirred for 2 hours. The mixture was concentrated in vacuo to remove the solvent. The residue was triturated with water (100 mL). The solid was collected by filtration, washed with a dilute solution of sodium thiosulfate and dried in vacuo to afford 3-bromo-5-ethanesulfonyl-pyridin-2-ol (9.1 g, 75%, two steps) as a white solid (reference: Bargar, T. M. et al., J. Heterocyclic Chem. 22 (1985) 1583-1592).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][C:8](N2CCCC2)=[C:7]([C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:18](C)C)[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+]>C(O)C>[OH:26][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:18]=[C:8]2[CH2:9][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]=12
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C1=C(N2CCCC2)CN(C(=O)OC)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OC)C2

Procedure:
A solution of 10.96 g of N-methoxycarbonyl-3-(2-ethoxycarbonyl-3-dimethylaminoacryloyl)-4-pyrrolidino-2,5-dihydropyrrole and 20 g of ammonium acetate in 250 ml of dry ethanol is refluxed for 90 minutes. The solution is cooled in an ice bath and the precipitate is filtered off to yield ethyl 4-hydroxy-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate, mp 274°-6° (dec); NMR (CF3COOD): 11.08 (s), 9.14 (s), 5.20 (s), 5.00 (s), 4.65 (q), 3.99 (s) and 1.52 (t).