Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]([S:14][CH3:15])=[S:13].II>CS(C)=O>[CH3:10][N:5]1[C:4](=[O:11])[C:3]2=[C:12]([S:14][CH3:15])[S:13][N:1]=[C:2]2[N:7]([CH3:8])[C:6]1=[O:9]
Reactant: CSC(=S)c1c(N)n(C)c(=O)n(C)c1=O
Agent: II
Solvent: CS(C)=O
Product: CSc1snc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
The mixture of step 1 intermediate (15.0 g, 60.64 mmol) and iodine (15.39 g, 60.64 mmol) in dry DMSO (250 ml) was heated at 100° C. for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature and quenched into water (200 ml), solid separated out was filtered and washed with saturated solution of sodium thiosulphate (150 ml), water (100 ml) and dried to obtain 13.4 g as an off white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 3.18 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 82 %

Procedure:
(a)(b) To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (800 mg, 2.5 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (1 mL, 6.25 mmol) in 30 mL of dry DCM was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoat. Crude methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 770 mg (82% yield, 2 steps) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid which could be separated into its four isomers by chiral HPLC. MS found: (M+H)+=375.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O.[Cl-].[NH4+]>CN(C=O)C>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])=[N:3][CH:4]=1
Reactant: Nc1ccncn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(I)cn2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccncn1)N1CC(Oc2ccc(I)cn2)C1
Reaction time: 0.08 h
Yield: 64.7 %

Procedure:
A solution of 4-aminopyrimidine (Aldrich, 243 mg, 2.54 mmol) in anhydrous DMF (4 mL) was added via syringe to a suspension of sodium hydride (60 wt % dispersion in mineral oil, 185 mg, 4.62 mmol) in anhydrous DMF (4 mL) under a nitrogen atmosphere. The mixture was stirred for 5 min. then a solution of 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (1.02 g, 2.31 mmol) in anhydrous DMF (6 mL) was added drop-wise and the resulting yellow coloured turbid mixture was stirred at ambient temperature for 1.5 hr. The reaction mixture was poured into sat. aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with sat. aqueous sodium chloride solution (100 mL) and dried over sodium sulphate. The mixture was filtered and the filtrate solvents removed in vacuo to afford a yellow solid, which was triturated with diethyl ether, filtered and dried to afford the title compound (594 mg, 65%) as a colourless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([NH:22][C:23](=[O:27])[C:24]([OH:26])=O)=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:28].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([NH:22][C:23](=[O:27])[C:24](=[O:26])[NH:37][S:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:28]
Reactant: O=C(O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Reactant: NS(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2)C(=O)NS(=O)(=O)c1cccs1

Procedure:
A mixture of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxalamic acid, I-62 (52 mg, 0.14 mmol), thiophene sulfonamide (28 mg, 0.17 mmol), EDCI (33 mg, 0.17 mmol), DMAP (22 mg, 0.17 mmol) in methylene chloride was stirred at room temperature for 24 h. Reaction was diluted with chloroform (10 mL) and washed with 6.0 M HCl (3.0 mL×4), water (3.0 mL). Chloroform layer was concentrated and the residue was purified over silica gel with chloroform:methanol (90:10) as eluant to afford N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-2-oxo-2-(thiophen-2-sulfonylamino)-acetamide, P019 (7.0 mg). 1H NMR (500 MHz, DMSO-d6) 4.59 (s, 2H), 5.35 (s, 2H), 6.84 (dd, J=8.0, 1.5 Hz, 1H), 6.90 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (m, 2H), 7.06 (dd, J=5.0, 3.5 Hz, 1H), 7.44 (m, 1H), 7.56 (s, 1H), 7.61 (dd, J=3.5, 1.5 Hz, 1H), 7.71-7.65 (m, 3H), 7.78 (m, 1H), 10.05 (s, 1H). MS (ESI−) Calcd. (M+) 521.6; Found: 520.7 (M−1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.O[N:13]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:13])=[O:11]
Reactant: O=C(O)Cc1ccccc1I
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCl (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and the organic layer were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I38) (1.755 g, 88% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 2H), 7.02-6.94 (m, 2H), 3.55 (s, 2H). LCMS Method C: rt 4.77 min; m/z 262.0 [M+H]+.
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C.[OH-].[Na+]>CO>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([C@@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:18]1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 2.4 g of (2R,5R)-2-(t-butyl)-5-((1R)-3,3-difluorocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of methanol, 10 ml of a 1N aqueous solution of sodium hydroxide was added, followed by stirring for 3 hours at room temperature. After distilling the methanol off under reduced pressure, the reaction mixture was diluted with water, and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether, while the organic layer was dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure gave 1.66 g of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)S(O[CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>C1C=CC=CC=1.C(COC)OC>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
First, 3.0 g of 60% sodium hydride and 120 ml of dehydrated dimethoxyethane were put in an argon-replaced 300 ml flask. Then, 9.93 g of 4,4′-dihydroxybiphenyl was added while icing, and stirred at room temperature for two hours. The reaction solution was cooled again to −60° C., and 28.7 g of 2-(perfluorobutyl)ethyl trifluoromethanesulfonate was dropped into the reaction solution. After the resultant reaction solution was left to resume room temperature, it was stirred for 12 hours. After the reaction, dilute hydrochloric acid and benzene were added to the reaction solution to separate an organic layer. The organic layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:benzene/ethyl acetate=9/1), and recrystallized from toluene to obtain 6.26 g (Y: 27.1%) of 4-hydroxy-4′-[2-(perfluorobutyl)ethyloxy]biphenyl. The purity of the resultant compound was 98.4% as measured by GC.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:14]([C:16]1[CH:24]=[C:23]([F:25])[C:19]([C:20](Cl)=[O:21])=[C:18]([F:26])[CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([F:26])[C:19]([C:20]([C:3]2[C:4]3[C:5](=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:21])=[C:23]([F:25])[CH:24]=1)#[N:15]
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(F)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CC(=O)Nc1nccc2c(C(=O)c3c(F)cc(C#N)cc3F)c[nH]c12

Procedure:
N-[3-(4-Cyano-2,6-difluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]acetamide (Compound No. 53) was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 4-cyano-2,6-difluoro benzoyl chloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:14]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:12]([N:14]1[C:18]([O:19][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:17][C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:15]1)[CH3:13]
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
1,4-difluoro-2-nitrobenzene (2.06 g, 9.85 mmol, 3 equiv) was added to a stirring mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (0.70 g, 3.28 mmol, 1 equiv) and potassium carbonate (1.36 g, 9.85 mmol, 3 equiv) in DMSO (6.57 mL). The reaction mixture was stirred at 80° C. for 20 minutes then cooled to 22° C. and diluted with water. The mixture was extracted with ethyl acetate, and then the organic layer was washed sequentially with water (two times) and saturated aqueous sodium chloride. The washed solution was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo to give the 3-[1-ethyl-5-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-3-yl]benzonitrile. The crude reaction product was taken into the next step without further purification. Calcd (M+1)+: 353.1. Found: 353.2.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[CH:23][C:24]=1[O:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)#[N:27]
Reactant: N#Cc1cc(N)ccc1OCCN1CCOCC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(OCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 60.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.74 g) synthesized according to Starting Material Synthesis Example 88 and 5-amino-2-(2-morpholinoethoxy)benzonitrile (0.95 g), the title compound (0.78 g) was obtained, melting point: 191–193° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
103 mg of solid yellow 3-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-chloro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:16]([C:26]([OH:28])=[O:27])[CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2].[N+](=[CH2:38])=[N-]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:16]([C:26]([O:28][CH3:38])=[O:27])[CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-nitro-2-[(1-carboxy-4-piperidinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-nitro-2[[1-(methoxycarbonyl)-4-piperidinobutylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:28])=[O:27])[C:7]([C:36]#[N:37])=[C:6]([CH3:38])[NH:5][C:4]=1[CH3:39])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:28])=[O:27])[C:7]([C:36]#[N:37])=[C:6]([CH3:38])[NH:5][C:4]=1[CH3:39])#[N:2]
Reactant: CCOC(=O)CCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCS(=O)(=O)Nc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
41 mg (0.073 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-{[(3-ethoxy-3-oxopropyl)sulfonyl]amino}-1H-indazole-1-carboxylate (Example 19A) were dissolved in dichloromethane (4 ml) and treated with 0.062 ml (0.8 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 33 mg (98% of th.) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=1[OH:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(I)cc1O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-hydroxy-4-iodo-benzoic acid (4.0 g, 0.015 mol) in THF (25 ml) and MeOH (25 ml) is treated by the dropwise addition of (trimethylsilyl)-diazomethane (2.0M in Et2O, 15 ml) and stirred at room temperature for 2.5 hours. Volatiles are removed in vacuo and the crude residue diluted into EtOAc. The organic phase is sequentially washed with saturated aqueous NaHCO3 (3×), saturated aqueous NaCl (1×), and H2O (1×). The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (0-80% ethyl acetate in hexanes gradient) to afford 2-hydroxy-4-iodo-benzoic acid methyl ester: ESMS m/z 279.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:34][C:31]3[CH:30]=[N:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[O:16])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-methoxy-5-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-methoxypyridin-3-yl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:19][CH2:20][CH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[C@H:31]2[C@H:35]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:34]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:33]([CH2:52][O:53][CH3:54])[O:32]2)=[C:24]([NH:55][CH2:56][CH:57]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:23]=1.[CH2:70]([C:72]([CH2:74][CH3:75])=O)[CH3:71]>ClCCl.C(OCC)(=O)C>[Si:37]([O:36][C@@H:35]1[C@H:34]([O:44][Si:45]([C:48]([CH3:49])([CH3:50])[CH3:51])([CH3:47])[CH3:46])[C@@H:33]([CH2:52][O:53][CH3:54])[O:32][C@H:31]1[N:28]1[CH:27]=[N:26][C:25]2[C:29]1=[N:30][C:22]([CH2:21][CH2:20][NH:19][CH:72]([CH2:74][CH3:75])[CH2:70][CH3:71])=[N:23][C:24]=2[NH:55][CH2:56][CH:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Sodium triacetoxyborohydride (105 mg, 0.51 mmol) and glacial acetic acid (24 mg, 0.40 mmol) were added to a stirred solution of N-{2-(2-aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl}-N-(2,2-diphenylethyl)amine (250 mg, 0.34 mmol) (preparation 18) and diethyl ketone (58 mg, 0.68 mmol) in dichloromethane (15 ml) and the resulting mixture stirred under an atmosphere of nitrogen gas at room temperature overnight. Additional portions of diethyl ketone (30 mg, 0.35 mmol) and sodium triacetoxyborohydride (60 mg, 0.29 mmol) were then added and stirring continued at room temperature for a further 24 hr. The mixture was diluted with ethyl acetate (20 ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, brine and water. The organic phase was separated and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4) to give the title compound (250 mg) as a gum. MS: 803 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.F[C:10]1[C:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:17]=2)=[CH:14][C:13]([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][C@@H:44]2[CH3:53])=[CH:12][N:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:14][C:13]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:50])=[O:51])[CH2:45][C@@H:44]3[CH3:53])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: Nc1ccc(Cl)nc1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cnc2Nc2ccc(Cl)nc2)n1

Procedure:
The title compound was prepared from 6-chloropyridin-3-amine (Sigma Aldrich, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 504 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H) 8.88 (d, J=2.74 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 8.47 (dd, J=8.71, 2.84 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 7.93 (br. s., 1H) 7.78 (br. s., 1H) 7.45 (d, J=8.61 Hz, 1H) 3.94 (d, J=13.11 Hz, 1H) 3.07-3.29 (m, 3H) 2.86-2.97 (m, 1H) 2.85 (s, 3H) 2.64-2.79 (m, 2H) 2.54-2.64 (m, 1H) 2.45 (s, 3H) 2.14-2.29 (m, 1H) 1.16 (d, J=6.06 Hz, 3H).