Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].C(O)(=[O:17])C.N([O-])=O.[Na+]>O>[OH:17][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc2c(c1)CCO2
Temperature: 65 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (200 mg, 1.04 mmole) is dissolved in 250 mg (4.14 mmole) of glacial acetic acid and 145 mg (2.08 mmole) of sodium nitrite in about 5 ml of water is added dropwise. An additional 1 ml of glacial acetic acid is added and the mixture is heated to 65° C. and held at 65° C. for 4 hours. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate for several hours. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give a 65% yield of the title compound. NMR(DMSO-D6)ppm(δ)7.15(m,3); 5.18(d,1); 4.78(t,2) and 3.34(t,2).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C1COCC1.[CH3:11][N:12]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH2:16]1)[CH3:13].C(N(CC)CC)C>C(=O)(O)[O-].[K+]>[CH3:13][N:12]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16]1)[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CC1CNc2ccccc2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC1Cc2ccccc2N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
Methanesulfonyl chloride (0.6 g) was added to a THF (20 ml) solution of 3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline (Reference Example 44; 1 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added triethylamine (2 ml), and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was diluted with a saturated aqueous potassium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate) and recrystallized from IPE to obtain the entitled compound (1 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCCl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([Br:1])[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)C(Br)c1ccc(Cl)c(Cl)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 106.9 %

Procedure:
N-bromosuccinimide (116 g, 1.4 equivalent amounts) was added to a 1,2-dichloroethane (320 mL) solution of methyl 2-(3,4-dichlorophenyl)acetate (106.8 g, 0.446 mol) at room temperature, followed by heating to 85° C. To this solution, a 1,2-dichloroethane (22.6 mL) solution of benzoyl peroxide (2.26 g, 2.0 mol %) was dropwise added dividedly 10 times every 10 minutes, followed by stirring at 85° C. for 3 hours. The reaction solution was cooled to room temperature, sequentially washed with a 2M sodium hydroxide aqueous solution, a mixed liquid of water-sodium thiosulfate aqueous solution (2:1, (v/v)), a saturated ammonium chloride aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a brown oil (142 g, yield: 103%).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH3:17][CH:18]([Zn+])[CH3:19].[OH-].[Na+]>>[CH:18]([C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:15])([CH3:19])[CH3:17]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Reactant: CC(C)[Zn+]
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
In analogy to the procedure described for the synthesis of example B.10, the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid methyl ester and 2-propyl zinc bromide followed by saponification with sodium hydroxide. MS (m/e): 231.0 (M−H)
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][CH2:10][CH:9]2[CH:5]([CH:6]=[N:7][N:8]2[CH3:12])[C:4]1=O.[OH:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]([NH2:24])=[NH:23])[CH:18]=[CH:19][CH:20]=1>CN(C=O)C>[CH3:12][N:8]1[C:9]2[CH2:10][CH2:11][C:3]3[CH:2]=[N:23][C:22]([NH:21][C:17]4[CH:16]=[C:15]([OH:14])[CH:20]=[CH:19][CH:18]=4)=[N:24][C:4]=3[C:5]=2[CH:6]=[N:7]1
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: CN1N=CC2C(=O)C(=CO)CCC21
Solvent: CN(C)C=O
Product: Cn1ncc2c1CCc1cnc(Nc3cccc(O)c3)nc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To the DMF solution of crude 5-hydroxymethylene-1-methyl-1,3a,5,6,7,7a-hexahydro-indazol-4-one was added 10 eq of N-(3-hydroxy-phenyl)-guanidine, the reaction mixture was stirred at 100° C. for overnight, LC/MS indicated one of the two peaks is the desired product. The DMF solution of reaction mixture was directly injected into prep HPLC, only a portion of the product mixture was purified.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16]C=2N=N1.N1CCCCC1.C[N:35]([CH:37]=[O:38])C>O.ClCCl>[N:8]1([C:37]([NH2:35])=[O:38])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C)C=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: C1CCNCC1
Product: NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
The synthesis of compound 61 was carried out according to scheme 13 beginning with commercially available pyrazolo[1,5-a]pyridine-3-carboxylic acid and by following the procedure outlined in example 1, part C, step 2 and subsequent steps though step E, part 1. The thiazole 5-position was left unfunctionalized by omitting part D, step 3 to obtain with the carboxylic acid 57. To carboxylic acid 57 (725 mg, 2.96 mmol) in DMF (30 mL) was added BOP (392 mg, 8.87 mmol) and piperidine (2.93 mL, 29.6 mmol). The reaction was stirred at ambient temperature for 48 hrs after which time the reaction was diluted with water and dichloromethane. The organic was washed with water before concentration. The resultant residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in hexanes, linear gradient) to yield the piperidine amide (739 mg, 2.366 mmol, 80% yield). The amide (420 mg, 1.34 mmol) was dissolved in dichloromethane (1.3 mL) was treated with potassium nitrate (136 mg, 1.344 mmol) and sulfuric acid (215 μL, 4.03 mmol). The reaction mixture was stirred at RT until complete, as judged by LCMS analysis. The reaction was quenched with 1N potassium hydroxide in methanol, then diluted with water, before extracting with dichloromethane. The organic layer was evaporated to dryness and taken up in methanol. The product was collected by filtration and was dried under reduced pressure to yield compound 58 (225 mg, 0.630 mmol, 46.8% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]2[CH2:25][CH2:26][NH:27][CH2:28][C:21]=2[CH:20]=1.C(N(CC)CC)C.O>C(Cl)CCl>[C:1]([N:27]1[CH2:26][CH2:25][C:22]2[N:23]=[N:24][C:19]([Cl:18])=[CH:20][C:21]=2[CH2:28]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1

Procedure:
A mixture of 12.6 g of benzoyl chloride in 100 cc of ethylene chloride is added dropwise to a suspension of 25.6 g of 3-chloro-5,6,7,8-tetrahydropyrido [4,3-c]pyridazine maleate in 250 cc of ethylene chloride and 21.8 g of triethylamine within 18 minutes at room temperature while stirring. The mixture is stirred at room temperature for a further 14 hours, 200 cc of water are added, the organic phase is separated and concentrated to an oil in a vacuum. Upon adding ether/dimethoxyethane to this oil, crude 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine is obtained. After recrystallization from absolute ethanol with the addition of a small amount of coal, the compound has a M.P. of 125°-127° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][OH:17])[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C)c(CCO)n2)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(OC)cc4)ccc3C)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of 2-[6-(4-methoxyphenyl)-3-methyl-2-pyridinyl]ethanol (Example 480, 0.15 g, 0.62 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.11 g, 51 mmol) in THF (2.50 mL) were added triphenylphosphine (0.17 g, 0.67 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.18 g, 67 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and concentrated under reduced pressure. The title compound (0.094 g, 41%) was isolated after silica gel chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.96 (d, 2H), 7.53-7.45 (m, 2H), 7.05 (d, 1H), 6.96 (d, 2H), 6.85-6.80 (m, 1H), 6.73 (dd, 1H), 4.48 (t, 2H), 4.14 (q, 2H), 3.86 (s, 3H), 3.51 (qt, 1H), 3.30 (t, 2H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.45-2.33 (m, 5H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][Cl:24].C(=O)([O-])O.[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:24][CH2:23][CH2:22][N:8]1[C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCBr
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1CCCl
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-nitro-2H-1,4-benzoxazine-3(4H)-one (2.0 g), benzyltriethylammonium chloride (470 mg), potassium carbonate (4.27 g) and acetonitrile (60 mL), 1-bromo-2-chloroethane (1.28 mL) was added and stirred at 75° C. for 3 hours. After the reaction liquid was cooled, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (1.92 g) as a yellow powder.
Reaction SMILES: C([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)(C)(C)C.[OH-].[K+].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([C:33](=[O:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>CCO>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([C:33](=[O:35])/[CH:34]=[CH:15]/[C:12]3[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:17])=[N:10][CH:11]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)c1cccc(N2CCN(C)CC2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 190 mg, 0.81 mmol), KOH 1.7 M (0.716 ml, 1.22 mmol) and 1-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (177 mg, 0.812 mmol) in EtOH (8 ml) was stirred at 0° C. for 4 h. The resulting slurry was partitioned between water and AcOEt and the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 98:2:0.2). The collected fractions were evaporated and the resulting powder was dissolved in DCM (10 ml) and TFA (1 ml). The solution was stirred at room temperature for 72 h. The solvent was then removed and the residue was triturated in Et2O to give 164 mg (E)-3-(5-{(E)-3-[3-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(CO)(CC1CCCCC1)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 2-cyclohexylmethyl-2-hydroxymethyl-malonic acid diethyl ester (1.31 g, 4.13 mmol) in methylene chloride (20 mL) and triethyl amine (1.16 mL, 8.00 mmol) was cooled to −40° C. A solution of methylsulfonyl chloride (0.402 mL, 5.2 mmol) in methylene chloride (4 mL) was added to the reaction mixture over 5 minutes. The reaction mixture was warmed to −10° C. over 1 hour and then poured into cold dilute aqueous HCl. The product was extracted with ethyl acetate, the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.505 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[O:12]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18](C=O)[CH:19]=[CH:20][C:13]1=2>>[O:12]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])[CH:19]=[CH:20][C:13]1=2
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCO3)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.9 mg (0.29 mmol) of 2,3-dihydrobenzo[b]furan-5-carboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C16H17NO3S2, 336.07 (M+H), found 334.3 (imine), 335.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:34]2[CH:35]=[C:30]([Cl:29])[C:31]([OH:46])=[C:32]([Cl:45])[CH:33]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 55.1 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(2-(dimethylamino)ethyl)phenyl amino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (66 mg, 55%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.23 (s, 2H), 3.40 (m, 2H), 3.22 (m, 2H), 2.98 (s, 6H), 2.90 (m, 1H), 1.22 (m, 4H); ESI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC 97.6% (AUC), tR=11.15 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:17]([OH:21])[C:18]([CH3:20])=[CH2:19])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=C(C)[C@@H](O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
This compound was prepared from ketone 67 (0.70 g, 1.85 mmol) in a synthetic procedure similar to that for compound and obtained after column chromatography (10%->25% EtOAc/PE) as a colorless oil (yield: 0.71 g, 1.85 mmol, quant.). 1H NMR (400 MHz, CDCl3): δ=7.32-7.18 (m, 7H), 7.04 (d, J=8.15 Hz, 2H), 6.77 (s, 1H), 5.17 (d, J=9.01 Hz, 1H), 5.05-4.91 (m, 4H), 4.14-4.10 (m, 1H), 4.05-3.97 (m, 1H), 3.01 (s, 1H), 2.86-2.78 (m, 1H), 2.64 (dd, J=14.18, 9.64 Hz, 1H), 1.76 (s, 3H), 1.50 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=156.03, 152.82, 144.45, 136.48, 136.33, 132.60, 129.65, 128.24, 127.79, 127.70, 118.49, 112.28, 80.17, 76.61, 66.37, 54.06, 33.46, 28.20, 18.71 ppm. [α]D23=−13.8 (c=1, CHCl3). HRMS: calcd. for C25H32N2O5 441.23840 [M+H]+. found 441.23843.
Reaction SMILES: Cl.[Si]([O:9][CH:10]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH:13]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:14]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[C:16](=[O:17])[CH:13]([CH2:12][CH2:11][CH:10]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[OH:9])[CH:14]2[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1cccc(C#N)c1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reaction time: 12 h

Procedure:
10 ml of 1N hydrochloric acid are added to 7.8 g of 3-[3-[3-(tert-butyldimethyl-silanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]benzonitrile (13) in 200 ml of methanol, and the mixture is stirred for 12 h. Aqueous sodium bicarbonate solution is added to the reaction mixture, which is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/heptane=1/3->1/1). This gives 14: C25H20F2N2O2 (418.45) MS (ESI) 401 (M+H—H2O)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:17]2[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24]#[N:25])[CH:10]=2.[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.O.CCCCCC>[C:24]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[NH:1][CH2:30][CH3:31])[C:17]1[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:13][C:12]2=1)#[N:25]
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2N)C1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCNc1ccccc1Cn1c2c(c3cc(C#N)ccc31)CC(NC(=O)C(C)C)CC2
Temperature: 40 °C
Yield: 200.7 %

Procedure:
Dissolve N-[9-(2-amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 109) (193 mg, 0.5 mmol) in anhydrous DMF (2 mL) under nitrogen. Add acetaldhyde (0.34 mL, 0.6 mmol), sodium triacetoxyborohydride (191 mg, 0.9 mmol) and acetic acid (0.072 ml, 1.25 mmol) and heat at 40° C. for 6 h. Take TLC (1 hexane/3 ethyl acetate) and observe starting material is still present. Add more acetaldehyde (0.010 mL, 0.18 mmol), sodium triacetoxyborohydride (60 mg, 0.3 mmol) and acetic acid (0.030 mL, 0.5 mmol) and heat at 40° C. for 18 h. Observe TLC which shows the reaction still not complete 1 0 but new by-product is forming. Allow the reaction to cool, dilute with water (20 mL), and extract with ethyl acetate (3×20 mL). Combine the organic portions and wash with brine (40 mL), dry (MgSO4), filter, and concentrate in vacuo to give 416 mg of a brown solid. Absorb on silica with THF and a small amount of methanol and purify by flash chromatography. Elute with dichloromethane, then 10% ethyl acetate/dichloromethane with a gradient up to 50% ethyl acetate/dichloromethane to obtain 103 mg (50%) of a white solid. MS (ES): m/z 415 (M+1), 413 (M−1); 1H NMR(DMSO-d6): δ 8.02 (s, 1H), 7.88 (d, 1H, J=7.5 Hz), 7.41 (d, 2H, J=0.9 Hz), 7.07 (t, 1H, J=7.7 Hz), 6.67 (d, 1H, J=7.9 Hz), 6.42 (t, 1H, J=7.6 Hz), 5.85 (d, 1H, J=7.4 Hz), 5.25 (s, 2H), 5.06 (t, 1H, J=5.3 Hz), 4.04 (m, 1H), 3.17 (m, 2H), 3.04 (dd, 1H, J=15.4, 5.3 Hz), 2.74-2.55 (m, 3H), 2.41 (m, 1H), 1.97 (m, 1H), 1.83 (m, 1H), 1.28 (t, 3H, J=7.0 Hz), 1.02 (m, 6H).
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+]>CCO>[Br:3][C:4]1[CH:5]=[C:6]([C:7](=[N:1][OH:2])[NH2:8])[CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cccc(Br)c1
Temperature: 120 °C

Procedure:
Hydroxylamine (1.00 mL of a 50% aqueous solution, 16.3 mmol) was added to a solution of 3-bromobenzonitrile (750 mg, 4.12 mmol) and potassium carbonate (1.00 mg, 7.24 μmol) in EtOH (3.00 mL). The resulting mixture was heated to 120° C. in a sealed microwave vial for 40 min. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound i-3a. m/z (ES) 215 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:12][CH3:13])=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:21]2[C:20]([C:11]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)([O:12][CH3:13])[C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][CH:7]=3)=[C:28]3[C:23]([CH:24]=[C:25]([F:30])[C:26]([F:29])=[CH:27]3)=[N:22]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(C(OC)(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(c1ccc(C(=O)O)cc1)(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless foam. MS: m/e=511.3 [M+H+].