Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>CC(N(C)C)=O>[CH2:1]([N:4]([CH3:20])[C:5]([C:7]1[C:15]([I:16])=[C:14]([NH:17][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]=1[I:19])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
3-(Allyl-methyl-carbamoyl)-5-amino-2,4,6-triiodo-benzoyl chloride (8) (5 g, 7.93 mmol) was dissolved in dry DMA (20 mL) was acetoxyacetyl chloride (1.7 mL, 15.9 mmol) was added dropwise. The reaction mixture was stirred at overnight at RT, with nitrogen bubbling through the reaction mixture. The reaction was monitored by TLC on silica gel plates eluting with ethyl acetate: petrol (1:1). (6) had an Rf of 0.62 and 0.76 whilst there were two new spots at 0.32 and 0.22. The solution was diluted with ethyl acetate (˜100 mL) and washed with ice water/brine (50:50, 20 ml×5). The organics were dried over MgSO4, filtered, concentrated and dried under high vacuum to give the desired compound (5.26 g, 91%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1ccnc(CO)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccnc(COc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (4-methyl-pyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: COCC[O:5][C:6](=[O:98])[C:7]1[CH:19]=[C:18]([NH:20][C:21]([C:23]2[C:24]([C:75]([NH:77][C:78]3[CH:79]=[C:80]([C:91]([O:93]CCOC)=[O:92])[CH:81]=[C:82]([CH:90]=3)[C:83]([O:85]CCOC)=[O:84])=[O:76])=[CH:25][C:26]([C:52]([NH:54][C:55]3[CH:56]=[C:57]([C:68]([O:70]CCOC)=[O:69])[CH:58]=[C:59]([CH:67]=3)[C:60]([O:62]CCOC)=[O:61])=[O:53])=[C:27]([C:29]([NH:31][C:32]3[CH:33]=[C:34]([C:45]([O:47]CCOC)=[O:46])[CH:35]=[C:36]([CH:44]=3)[C:37]([O:39]CCOC)=[O:38])=[O:30])[CH:28]=2)=[O:22])[CH:17]=[C:9]([C:10]([O:12]CCOC)=[O:11])[CH:8]=1.CN(C)C=O.[OH-].[Na+:105]>C(O)C>[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[C:24]1([C:75]([NH:77][C:78]2[CH:79]=[C:80]([C:91]([O-:93])=[O:92])[CH:81]=[C:82]([CH:90]=2)[C:83]([O-:85])=[O:84])=[O:76])[CH:25]=[C:26]([C:52]([NH:54][C:55]2[CH:56]=[C:57]([C:68]([O-:70])=[O:69])[CH:58]=[C:59]([CH:67]=2)[C:60]([O-:62])=[O:61])=[O:53])[C:27]([C:29]([NH:31][C:32]2[CH:33]=[C:34]([C:45]([O-:47])=[O:46])[CH:35]=[C:36]([CH:44]=2)[C:37]([O-:39])=[O:38])=[O:30])=[CH:28][C:23]=1[C:21]([NH:20][C:18]1[CH:17]=[C:9]([C:10]([O-:12])=[O:11])[CH:8]=[C:7]([CH:19]=1)[C:6]([O-:98])=[O:5])=[O:22]
Reactant: COCCOC(=O)c1cc(NC(=O)c2cc(C(=O)Nc3cc(C(=O)OCCOC)cc(C(=O)OCCOC)c3)c(C(=O)Nc3cc(C(=O)OCCOC)cc(C(=O)OCCOC)c3)cc2C(=O)Nc2cc(C(=O)OCCOC)cc(C(=O)OCCOC)c2)cc(C(=O)OCCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C([O-])c1cc(NC(=O)c2cc(C(=O)Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)c(C(=O)Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)cc2C(=O)Nc2cc(C(=O)[O-])cc(C(=O)[O-])c2)cc(C(=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 8.23 g of the product of Example 1 and 45.0 ml of dimethylformamide is warmed until solution is achieved. The solution is cooled to room temperature and 90.0 ml of 1N sodium hydroxide is added with stirring. The solution is stirred for 20 minutes and diluted with 250 ml of ethanol. The product is collected and washed with ethanol and ether to yield a pale yellow powder. The product is purified by a series of precipitations from 28.6% aqueous ethanol, then from 33.3% aqueous ethanol, and is dried to yield 1.67 g of the product of the Example as a pale yellow powder.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)[C:14]=1[CH3:15])=[O:9])C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[C:14]([CH3:15])=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)=[N:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cn2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(C)C)cn1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Isopropylbromide (164 μl) was added to a suspension of 1-(5-hydroxypyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (333 mg) and potassium carbonate (558 mg) in N,N-dimethylformamide (1.5 ml) and stirred at 80° C. for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was reacted and treated in a similar manner as Reference Example 24(3) to give the titled compound (152 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCCO)=NCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(C#N)SCCOC(C)=O)=NCC2

Procedure:
To 1.0 g. of α(2-hydroxyethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 5 ml. of acetic anhydride and 15 ml. of benzene are added and the reaction mixture is refluxed for 4 hours. The mixture is then evaporated to dryness and to the residue carbon tetrachloride is added. 0.6 g. of α-(2-acetoxyethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 157° C. after recrystallization from butanol.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 194 (see example 156) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-methylimidazole
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:21])C=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])=[O:21])=[CH:4][CH:3]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
4.06 g (20 mmol) of 4-bromothioanisole and 75 ml of dichloromethane were introduced into a round-bottomed flask and 6.3 g (20 mmol) of meta-chloroperbenzoic acid were added. Stirring was carried out at room temperature for four hours and the reaction mixture was poured into water. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). After evaporating the solvents, 1.22 g (28%) of the expected sulfoxide, with a melting point of 80°-81° C., was recovered.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[C:10]1[C:19](OCC)=[O:20].O.[NH2:26][NH2:27].Cl>C(O)C>[C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[C:10]2[C:19](=[O:20])[NH:26][NH:27][C:14](=[O:15])[C:11]=2[CH:12]=[CH:13]1
Reactant: NN
Reactant: CCOC(=O)c1ccn(-c2c(C)cc(C)cc2C)c1C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-n2ccc3c(=O)[nH][nH]c(=O)c32)c(C)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
A mixture of diethyl 1-mesityl-1H-pyrrole-2,3-dicarboxylate (3.4 g, 10.3 mmol), hydrazine monohydrate (2.0 ml, 41.3 mmol) and ethanol (20 ml) was heated under reflux for 48 hours. The mixture was acidified by addition of 5N hydrochloric acid and stirred at 80° C. for 20 min. After cooling, the crystals were collected by filtration to give 2.60 g (94%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.O=[C:9]1[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:9]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]2)=[N:5][N:6]=1
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: Cc1nnc(N)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 81.4 %

Procedure:
To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[PH:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].CCN(CC)CC>C1(C)C=CC=CC=1.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>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[P:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)PC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)P(C1=Cc2ccccc2C1)C(C)C

Procedure:
Following the procedure described for the synthesis of 3 (method A), 15.81 g (0.081 mol) of 2-bromo-1H-indene, 9.54 g (0.081 mol) of iPr2PH, 13.9 ml (10.09 g, 0.100 mol) of Et3N, and 2.95 g (2.55 mmol) of Pd(PPh3)4 in 60 ml of toluene gave 1H-Inden-2-yl(diisopropyl)phosphine. The crude product was distilled in vacuum (104–106° C./2 mm). Yield 14.8 g (80%) of colorless oil of 1H-Inden-2-yl(diisopropyl)phosphine, 4.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][S:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:12])=[O:11])[CH3:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26].Cl>C1COCC1>[CH2:7]([N:9]1[C:25](=[O:26])[C:24]([OH:30])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[S:10]1(=[O:11])=[O:12])[CH3:8]
Reactant: CCNS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C(=O)C(O)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Temperature: 150 °C
Yield: 81.6 %

Procedure:
Potassium tert-butoxide (0.309 g, 1.83 mmol) was added to a solution of N-ethyl-1-[4-(trifluoromethyl)phenyl]methanesulfonamide (0.49 g, 1.83 mmol) and diethyl oxalate (0.322 g, 2.20 mmol) in THF (4 mL) at 0° C. The mixture was heated in a microwave reactor at 150° C. for 10 mins. HCl (1M, 2 mL) was added dropwise to the mixture at 0° C. It was evaporated and the residue was extracted with DCM. The organic layer was dried and evaporated to give the title compound (0.480 g, 81%) as a solid; 1H NMR (500 MHz, CDCl3): δ 8.05 (d, 2H), 7.77 (d, 2H), 3.87 (q, 2H), 1.49 (t, 3H); Mass Spectrum: M−H+ 320.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][C:19]1[C:24](B(O)O)=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][C:19]1[C:24]([Pb+3:17])=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Temperature: 40 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of lead tetraacetate (4.3 g, 9.7 mmol) in dry chloroform (15 ml) at 40° C. is added 3,5-dimethylbiphen-4-ylboronic acid (2.0 g; 8.8 mmol) in one portion under an atmosphere of nitrogen. The mixture is stirred at 40° C. for 4 hours, and then is cooled to room temperature. The precipitate is removed by filtration, and the filtrate is then passed through a plug of potassium carbonate supported on diatomaceous earth to remove acetic acid. The filtrate is evaporated in vacuo to afford 3,5-dimethylbiphen-4-yllead triacetate (3.37 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:29]1([CH2:32][NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)[CH2:31][CH2:30]1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NCC4CC4)c3C2=O)ccc1OC
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (1.8 g, 4.5 mmol), cyclopropane carboxaldehyde (0.47 mL, 6.3 mmol), and acetic acid (1.6 mL, 28 mmol) in 1,2-dichloroethane (20 mL), was added sodium triacetoxyborohydride (1.4 g, 6.7 mmol) at room temperature. After 1.5 hours, the mixture was extracted with methylene chloride (50 mL) and water (20 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 25 mL) and brine (25 mL), and dried over MgSO4. Removal of solvent gave a yellow oil, which was purified by prep HPLC to give (1S)-7-(Cyclopropylmethyl-amino)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one as a white solid (1.6 g, 79% yield): mp 147-149° C.; 1H NMR (CDCl3) δ 0.25-0.31 (m, 2H, CH2), 0.55-0.62 (m, 2H, CH2), 1.09-1.20 (m, 1H, CH), 1.45 (t, J=7 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2), 3.67 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, CHH), 4.29 (dd, J=10, 15 Hz, 1H, CHH), 4.34 (d, J=17 Hz, 1H, CHH), 5.62 (dd, J=5, 10 Hz, 1H, NCH), 6.47-6.55 (m, 2H, Ar), 6.69 (t, J=5 Hz, 1H, NH), 6.83 (d, J=8 Hz, 1H, Ar), 6.91-6.95 (m, 2H, Ar), 7.21-7.30 (m, 1H, Ar); 13C NMR (CDCl3) δ 3.57, 10.63, 14.71, 41.42, 47.52, 48.09, 52.04, 55.98, 56.39, 64.60, 108.35, 109.21, 111.48, 112.32, 113.77, 119.37, 130.45, 133.64, 142.78, 147.50, 148.79, 149.54, 171.16. Analy. calculated for C24H30N2O5S: C 62.86; H 6.59; N 6.11. Found: C 62.77; H 6.62; N 6.13.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:17]([C:21]1[NH:25][C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=1)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=[C:21]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Intermediate (2a) (13.6 g, 45 mmol, 1.0 eq), 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (8.4 g, 45 mmol, 1.0 eq) and potassium carbonate (12.4 g, 90 mmol, 2.0 eq) were added to 90 mL of DMF. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 300 mL EtOAc and extracted with 100 mL 10% aq. LiCl, 2×200 mL water, 100 mL saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was evaporated and purified by flash chromatography (40% EtOAc:hexanes) to yield intermediate (2b) (13.0 g). MS m/z: [M+H+] calcd for C19H26ClN3O3S, 412.1; found 412.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1([O:28][CH2:29][CH3:30])[CH2:25][NH:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:18]>>[CH2:29]([O:28][C:20]1([O:19][CH2:17][CH3:18])[CH2:25][N:24]([C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:16])[CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:30]
Reactant: CCOC1(OCC)CCC(CO)NC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: CCOC1(OCC)CCC(CO)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to general procedure A using 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid and rac-(5,5-diethoxypiperidin-2-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH:30]([NH:33][NH2:34])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:33]([CH:30]([CH3:32])[CH3:31])[N:34]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: CC(C)NN
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C(C)C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with isopropylhydrazine hydrochloride (CAS Reg. No. 16726-41-3) to give the title compound as yellow solid. MS (ESI): m/z=460.3 [M+H]+.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([CH2:58][C:59](O)=[O:60])#[N:57]>CN(C=O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:59](=[O:60])[CH2:58][C:56]#[N:57])[CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1
Reactant: O=c1[nH]ccc2nc(N[C@@H]3CCC[NH2+]C3)c3ccc(F)cc3c12
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H](Nc2nc3cc[nH]c(=O)c3c3cc(F)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)amino]piperidinium chloride (40 mg, 0.09 mmol) in DMF (2 mL) were added triethylamine (0.13 mL, 0.94 mmol), HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (36 mg, 0.094 mmol), and cyanoacetic acid (40 mg, 0.47 mmol). The solution was stirred at room temperature overnight. The crude solution was filtered and purified by reverse phase HPLC. LRMS (ESI) calc'd for (C20H19FN5O2) [M+H]+, 380.2; found 380.1.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:8][CH:9]=1)=[N+:2]=[N-:3].[C:20](OC=C)(=O)[CH3:21]>>[N:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:8][CH:9]=2)[CH:21]=[CH:20][N:3]=[N:2]1
Reactant: COc1ccc(COc2ccc(N=[N+]=[N-])cn2)cc1
Reactant: C=COC(C)=O
Product: COc1ccc(COc2ccc(-n3ccnn3)cn2)cc1
Temperature: 100 °C

Procedure:
5-Azido-2-(4′-methoxybenzyloxy)pyridine from step 2 of this example (55 mg, 0.215 mmol) and vinyl acetate (692 μl, 7.51 mmol) were mixed in a flame dried high pressure sealable vessel. The reaction vessel was evacuated and charged with nitrogen, sealed, and heated to 100° C. for 15 hours. The reaction was cooled to room temperature and TLC indicated that the reaction was complete. Minimal dichloromethane was added to the reaction (just enough to dissolve solids that formed upon cooling) and the solution added to a Biotage 25 g SiO2 column, eluting with 20-50% ethyl acetate/heptane to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](OC2C=CC=CC=2)=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Br:26])=[CH:21][C:20]=1[Cl:27].[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:31][CH2:28][CH:29]=[CH2:30])=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Br:26])=[CH:21][C:20]=1[Cl:27]
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2cc(Cl)c(Br)cc2Cl)cc1Oc1ccccc1
Reactant: C=CCN
Solvent: C1COCCO1
Product: C=CCNc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 7 h

Procedure:
A mixture of 4.9 gm of 2-chloro-4-nitro-5-phenoxy-1-(2,5-dichloro-4-bromo-phenoxy)-benzene, 1.8 gm of allylamine and 10 ml of dioxane was stirred first for 7 hours at 40° C. and then for 3 hours at 60° C. Thereafter, the reaction solution was evaporated, the residue was taken up in chloroform, and the resulting solution was washed first with an acid solution and then with an alkaline solution, dried with sodium sulfate and evaporated. The raw reaction product thus obtained (5.6 gm) was purified on a silicagel column, yielding 3.0 gm (66.6% of theory) of the yellow crystalline title compound, m.p. 102.5° C.