Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH2:18]>C(OC(C)C)(C)C>[CH2:16]([NH:19][C:20]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:21])[CH:17]=[CH2:18]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: C=CCN=C=O
Solvent: CC(C)OC(C)C
Product: C=CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 72 h
Yield: 27.5 %

Procedure:
A solution of 8.7 g (0.04 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 75 ml of isopropyl ether was stirred under a blanket of nitrogen while 4.2 g (0.05 mole) of 2-propenyl isocyanate was added dropwise. After stirring for 3 days, no crystalline product precipitated. The reaction mixture was concentrated to a dark reddish oil. TLC (20% ethyl acetate/methylene chloride on silica gel) showed at least 6 spots, all well separated. The residue was dissolved in chloroform, chromatographed on a 350 g silica gel column and eluted with chloroform until the reddish forerun was removed. The column was then eluted with an ethyl acetate/chloroform gradient to 4% ethyl acetate. All the fractions were combined and concentrated to give 4.8 of orange oil, which crystallized on standing. Recrystallization from acetone/cyclohexane gave 3.3 g (27.5%) of beige crystals, m.p. 91°-92.5° C.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH2:16][C:17]([C:19]1[CH2:23][CH:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[O:21][N:20]=1)=O>CO>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH:22]1[O:21][N:20]=[C:19]([C:17]2[N:1]=[C:2]([CH:3]3[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]3)[S:14][CH:16]=2)[CH2:23]1
Reactant: CCOC(=O)N1CCC(C(N)=S)CO1
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Solvent: CO
Product: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CO1

Procedure:
A solution of ethyl 5-(aminothioxomethyl)tetrahydro-2H-1,2-oxazine-2-carboxylate (i.e. the product of Step I) (0.19 g, 0.87 mmol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (the product of Example 1, Step C) (0.264 g, 0.87 mmol) in methanol (2 mL) was heated at 50° C. for 1 h. Methanol was removed under reduced pressure and the resulting material was partitioned between sodium acetate (10%, 5 mL) and diethyl ether (5 mL). The layers were separated and the aqueous phase was extracted with diethyl ether (2×). The organic fractions were concentrated under reduced pressure to provide the title compound as a pale-tan oil (0.383 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)C(=O)O
Solvent: CC(=O)O
Product: CCC(NC(C)=O)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
163 g (1.58 mol) 2-aminobutanoic acid are dissolved in acetic acid, and 242 g (2.37 mol) acetic anhydride are added dropwise. The mixture is stirred for 2 h at 100° C. until completion of reaction, then the solution evaporated to dryness in vacuo. The solid residue is suspended in ethyl acetate, filtered and washed with diethyl ether.
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH3:15]>ClCCl>[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([O:24][CH2:1][O:2][CH3:3])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CN1CCc1ccc(OC)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](OCOC)CN1CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
9.32 ml (123 mmol) of MOMCl was added to a solution of 25 ml (144 mmol) of N,N-diisopropylethylamine and 6.00 g (20.5 mmol) of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidine in dichloromethane (100 ml) and the mixture was stirred for 14 hours at room temperature. The mixture was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate : n-hexane=1:1 ) to give 6.20 g of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl) pyrrolidine in 89.8% yield.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]1[O:8][C:7]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:6]=2[O:5]1>>[CH2:2]([O:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH2:4][O:8][C:7]=2[CH:9]=1)[CH3:3]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCI
Product: CCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available iodoethane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: N1CCC(=O)NC1=O.[CH3:9][C:10]1(C2C=CC=CC=2)[NH:14][C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:23]3[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][O:26][C:22]=3[C:21]=2[CH2:35][CH2:36][CH3:37])[C:11]1=[O:38]>>[CH2:35]([C:21]1[C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]=2[CH:33]=[CH:34][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][N:12]1[C:11](=[O:38])[CH2:10][CH2:9][NH:14][C:13]1=[O:15])[CH2:36][CH3:37]
Reactant: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(-c3ccccc3)noc12
Agent: O=C1CCNC(=O)N1
Product: CCCc1c(OCCCN2C(=O)CCNC2=O)ccc2c(-c3ccccc3)noc12

Procedure:
3-(3-{[7-Propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared as for Example 10 from dihydropyrimidine-2,4(1H,3H)-dione and the bromide from Example 27. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:22]([O:23][CH3:24])=[CH:21][C:19]([NH2:20])=[C:18]([O:25][CH3:26])[CH:17]=1>>[Cl:15][C:16]1[C:22]([O:23][CH3:24])=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[C:18]([O:25][CH3:26])[CH:17]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(NC(=O)c2cc(C(N)=O)ccc2OC)c(OC)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-chloro-2,5-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[Cl:20]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][C:17]1[N:16]=[CH:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3cncn23)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)ncn23)c1
Temperature: 0 °C

Procedure:
To a solution of 0.01 mole of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine in chloroform is added 0.011 mole of N-chlorosuccinimide. The mixture is heated on a steam bath for one hour, cooled and poured into an ice-cold solution of 2.5 N sodium hydroxide. The organic layer is separated, dried (MgSO4) and passed through a column of hydrous magnesium silicate with chloroform as eluent. The eluent is concentrated to dryness to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=4[F:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=95%.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:48]=[CH:47][C:36]([CH:37]([NH2:46])[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([NH:46][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:36]2[CH:47]=[CH:48][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:39][CH:40]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccc(OC)cc2)cc1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4,4'-dimethoxybenzhydrylamine (prepared as described in Preparation 14) as starling materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 79%.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[NH:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:35]5[CH2:39][CH2:38][CH2:37][C:36]5=[O:40])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2N2CCNC2=O)CC1
Yield: 44.8 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (165 mg) described in Preparation Example 236 and pyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (75 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17](C=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH3:22])[CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNC1CCCCC1
Reactant: O=CC1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: CN(C1CCCCC1)C1CCN(c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 18 and N-methyl-N-cyclohexylamine.
Reaction SMILES: [N+](C1C=CC(S(O[C:14]2[C:25]3=[C:26]4[N:21]([CH2:22][CH2:23][CH2:24]3)[CH:20]=[C:19]([C:27]([OH:29])=[O:28])[C:18](=[O:30])[C:17]4=[CH:16][CH:15]=2)(=O)=O)=CC=1)([O-])=O.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[N:31]1([C:14]2[C:25]3=[C:26]4[N:21]([CH2:22][CH2:23][CH2:24]3)[CH:20]=[C:19]([C:27]([OH:29])=[O:28])[C:18](=[O:30])[C:17]4=[CH:16][CH:15]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn2c3c(c(OS(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc3c1=O)CCC2
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 14.4 %

Procedure:
20.0 g of 8-(p-nitrobenzenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 17 hours while stirring. Treatment in an analogous manner as in Example 15 gave 2.1 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:20]([C:11]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: c1ccc(COCn2ccnc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C(=O)c2nccn2COCc2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 3 h

Procedure:
A solution of 10.0 g of 1-[(benzyloxy)-methyl]imidazole in 50 ml of acetonitrile is added dropwise within 10 minutes while cooling with ice to a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g of triethylamine in 80 ml of acetonitrile so that the temperature does not exceed 25°. The mixture is subsequently stirred for an additional 3 hours, whereupon the solvent is distilled. After treatment with water, the mixture is extracted with ethyl acetate. After two-fold washing with water, the organic phase is dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 600 g of silica gel with toluene/ethyl acetate (95:5). There is obtained 1-[(benzyloxy)methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl) ketone as a yellowish oil
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([C:16]([CH3:18])=[CH2:17])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:23]([O:22][C:20]([NH:19][C@H:13]1[CH:14]([CH:16]([CH3:18])[CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: C=C(C)C1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C1CNC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A 10% palladium carbon catalyst (300 mg) was added to a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-isopropenylpyrrolidine (300 mg, 832 μmol) in methanol (10 mL), and the resultant mixture was stirred in a hydrogen atmosphere under an ordinary pressure for 2 hours. After filtration, a 10% palladium carbon catalyst (300 mg) was added again to the filtrate, followed by stirring in a hydrogen atmosphere under an ordinary pressure for 1 hour. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield (3S)-3-(tert-butoxycarbonyl)amino-4-isopropylpyrrolidine as a colorless amorphous (172 mg, quantitative amount).
Reaction SMILES: [CH2:1]([CH2:13]N)[CH2:2][C:3](P([O-])(O)=O)(P(O)(O)=O)[OH:4].[Na+:15].[OH-].[Na+].[N+:18]([C:21]1C=CC=[CH:26][C:22]=1C(Cl)=O)([O-])=O.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:38]([OH:41])([OH:40])=[O:39])([P:34]([OH:37])([OH:36])=[O:35])[OH:33]>O.C1COCC1>[NH2:18][C:21]1[CH:13]=[CH:1][C:2]([C:3]([NH2:43])=[O:4])=[CH:26][CH:22]=1.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:34]([O-:36])([OH:37])=[O:35])([P:38]([OH:41])([OH:40])=[O:39])[OH:33].[Na+:15]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-aminobenzamide of alendronate sodium was prepared as follows. In a 500 mL beaker, 54 g (166 mmol) of sodium alendronate was dissolved in 150 mL of DI water with a pH adjusted to 11 with concentrated NaOH. Nitrobenzoyl chloride, 28 g (150 mmol), dissolved in 100 mL of THF, was added dropwise into the aqueous alendronate solution. The pH was kept at 11 with additional NaOH solution during the addition. After the addition was complete, the solution was stirred for another 2 hours at room temperature. THF was removed in vacuo, and the pH of the solution was adjusted to 4. The resulting precipitate, which was collected by filtration at room temperature, was primarily nitrobenzoic acid and was discarded. The solution was kept at 4° C. overnight, and the resulting precipitate was collected by filtration, washed with DI water, and dried. The resulting solid weighted approximately 56 g (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[C:35]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:36])[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1
Reactant: CCOc1cccc(Nc2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [5-chloro-2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as colorless foam. MS: m/e=523.3 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.C(NCCN)[C:32]1[CH:37]=[CH:36]C=[CH:34][CH:33]=1>>[CH2:12]([NH:8][CH2:9][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:11]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCNCc1ccccc1
Product: O=C(NCCNCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.27 (1H, s) 8.05 (1H, t, J=5.47 Hz) 8.01 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.37 Hz) 7.46 (1H, d, J=5.47 Hz) 7.14-7.33 (7H, m) 6.80 (1H, d, J=5.56 Hz) 6.43 (1H, dd, J=3.42, 1.85 Hz) 3.69 (2H, s) 3.35 (2H, d, J=6.05 Hz) 2.65 (2H, t, J=6.59 Hz)
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1.O>CO>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C)c([N+](=O)[O-])cn1
Yield: 55.1 %

Procedure:
Sodium methoxide (26.1 g) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (19.0 g) in methanol (100 ml) and the resulting mixture was refluxed for 12 hours. Upon cooling, the mixture was poured over water (1 L), and the product was extracted with ethyl acetate and washed with water. The organic phase was dried (anhydrous magnesium sulfate) and concentrated, and the residue dissolved in hot ether and filtered. Crystallization from ether provided 10.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: O.[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 200 ml of water, 200 ml of ether and 20.0 g of 2-isopropylphenol was added dropwise 22.0 ml of 61% nitric acid, and then the mixture was reacted with stirring at room temperature for 2 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. After, the drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1:1)] to give 7.69 g of 6-isopropyl-2-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH:7]=1.[F:25][C:26]([F:42])([C:38]([F:41])([F:40])[F:39])[C:27]([C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)([F:29])[F:28]>[OH-].[Na+]>[CH3:19][C:16]1[C:15]([CH3:20])=[CH:14][C:13]2[O:12][C:8]3[C:9](=[CH:10][C:11]4[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:27]([F:29])([F:28])[C:26]([F:42])([F:25])[C:38]([F:41])([F:40])[F:39])[C:21]5[C:4]([O:5][C:6]=4[CH:7]=3)=[CH:3][C:2]([CH3:1])=[C:23]([CH3:24])[CH:22]=5)[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:27]([F:28])([F:29])[C:26]([F:42])([F:25])[C:38]([F:41])([F:40])[F:39])[C:18]=2[CH:17]=1
Reactant: Cc1ccc(Oc2cccc(Oc3ccc(C)c(C)c3)c2)cc1C
Reactant: O=C(c1ccccc1)C(F)(F)C(F)(F)C(F)(F)F
Agent: *CC*
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(cc1C)C(c1ccccc1)(C(F)(F)C(F)(F)C(F)(F)F)c1cc3c(cc1O2)Oc1cc(C)c(C)cc1C3(c1ccccc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 140 °C
Yield: 75.1 %

Procedure:
A mixture of 159 g (0.5 mole) 1,3-bis(3,4-dimethylphenoxy)benzene, 274 g (1.0 mole) phenyl heptafluoropropyl ketone, and 280 g (14 moles) HF was heated in an autoclave for 8 hours at 140° C. After cooling, and venting off excess HF, the autoclave contents were transferred to a 1-gallon polyethylene jar, half filled with ice water, and containing 500 ml of 50% sodium hydroxide. The autoclave was rinsed out with methylene chloride, and the washings were added to the jar. The product was extracted with methylene chloride, the extracts were filtered through a layer of alumina, and the solvent was stripped off at atmospheric pressure yielding 312 g of a taffy-like residue, which was very soluble in acetone. The residue was extracted with several 500 ml portions of boiling methanol, and then was stirred with isopropyl alcohol, producing a solid in 21.3 g (5.1 % yield) with a sharp IR spectrum, devoid of OH bands, and melting in the 198-220° C. range, and after recrystallization from heptane at 237-238° C. NMR of the product melting over the wide range showed presence of cis- and trans- isomers: aromatic protons as multiplets 7.05-7.25, 6.85-7.0, broad s 6.66, two broad singlets at 6.58 and 6.50, and methyl singlets at 2.20 and 2.02 ppm in 6:7:2:1(total of the 6.58 and 6.50 peaks): 6:6 ratio. The recrystallized material was a single isomer, by NMR m 7.1, m 7.0, s 6.94, s 6.86, broad s 6.65, broad s 6.47, s 2.23 and s 2.04 ppm in 4:6:2:1:2:1:6:6 ratio. Analysis: calc. for C42H28F14O2 : C 60.7; H 3.37, F 32.0; F 32.0; found C 70.0; H 3.61, F 30.1%.