Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][CH2:10][OH:11]>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][C:10]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: CCO
Product: O=c1cnc2ccccc2[nH]1

Procedure:
A mixture of the 1,2-phenylene-diamine derivative (1 g) and the 2-oxo-carboxylic acid derivative (1 eq) in dry EtOH (35 mL) was stirred at reflux for 2 h under nitrogen. After cooling, the EtOH was evaporated to give a crude brown solid. Recrystallisation from EtOH gave the desired quinoxalin-2-one derivative.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH3:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O>C1C=CC=CC=1>[CH2:6]([N:5]1[CH2:4][CH2:3][CH2:2][NH:1][CH:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[CH2:7][CH3:8]
Reactant: CCCNCCCN
Reactant: O=Cc1ccccn1
Solvent: c1ccccc1
Product: CCCN1CCCNC1c1ccccn1

Procedure:
To a stirred solution of 1,5-diazaoctane (16) (0.58 g, 0.005 mol) in dry benzene (20 mL) was added dropwise pyridine-2-carboxaldehyde (0.535 g, 0.005 mol) in dry benzene (10 mL). The resulting solution was refluxed for 2 hr using a Dean-Stark trap to remove water. Finally, the solvent was removed completely by distillation to give compound (17) in quantitative yield (1.0 g).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].CCCCCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=CC=CC=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(OCC)C>[C:1]1([Li:5])[C:22]2[CH2:23][C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
With stirring, 113 ml of a 1.6 M solution of n-butyllithium in hexane (0.18 mol) were added to a solution of 25 g (0.15 mol) of fluorene in 220 ml of diethyl ether. To bring the reaction to completion, the mixture was boiled under reflux for 6 h and then stirred at room temperature overnight. The solvent was subsequently removed under reduced pressure and the resulting yellow powder was washed repeatedly with petroleum ether and dried under reduced pressure. This gave fluorenyllithium (compound II) in almost quantitative yield.
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:36])[C:12]1[CH:17]=[C:16]([CH2:18][C:19]2[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=2[CH3:25])[CH:15]=[CH:14][C:13]=1[O:32]C(=O)C)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][N:2]([C:11](=[O:36])[C:12]1[CH:17]=[C:16]([CH2:18][C:19]2[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=2[CH3:25])[CH:15]=[CH:14][C:13]=1[OH:32])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Yield: 78.2 %

Procedure:
N-Methyl-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-methoxyaniline (0.070 g, 0.142 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.050 g, 0.111 mmol, 78%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:11][CH:12](O[Si](C(C)(C)C)(C)C)[CH2:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:10])[CH:11]=[CH:12][CH:13]=[C:14]1[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)n3Cc3ccccc3)C21

Procedure:
To a stirred solution of 200 mg (0.32 mmol) 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml methylene chloride are added 0.3 g (2.6 mmol) trifluoroacetic acid. After 2 hours at room temperature the reaction mixture is quenched with saturated aqeous sodium bicarbonate. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated. The residue is chromatographed over silica gel (hexane/ethyl acetate 7/3 to 2/3) affording the title compound as a white powder foam. MS (FAB) m/z 480 ([M+Li]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19]C=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].[NH2:39]C1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.C1(C2SC(C(OCC)=O)=NC=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][N:39]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Agent: CCOC(=O)c1ncc(-c2ccccc2)s1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cn3)cc2C1=O
Yield: 39 %

Procedure:
The compound of example 636 was prepared analogous to the compound of example 611 by reaction of compound of example 392 with ethyl 5-phenylthiazole-2-carboxylate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1C(C1C=CC(OCCCN(CCCC)CCCC)=CC=1)=O.C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1)CCC.[H][H]>[Pt]=O>[CH2:4]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH2:14])=[CH:8][C:7]=2[CH:6]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Product: CCCCc1cc2cc(N)ccc2o1

Procedure:
A process for synthesizing dronedarone was described in patent application WO 02/48132, mentioned previously, using 2-n-butyl-5-nitrobenzofuran, which is reduced, under pressure with hydrogen in the presence of platinum oxide as catalyst to form 2-n-butyl-5-aminobenzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamidobenzofuran, which is treated with 4-[3-(di-n-butylamino)propoxy]benzoyl chloride to obtain dronedarone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([CH2:15][N:11]1[CH:12]=[CH:13][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)#[N:17]
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCn1ccc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
3.0 g of 3-(2,6-difluorophenyl)pyrazole was dissolved in 20 ml of acetonitrile, and 2.52 g of chloroacetonitrile and 4.61 g of potassium carbonate were added thereto at room temperature, and heated under reflux for 5 hours. After acetonitrile was distilled off under reduced pressure, ethyl acetate was added to the residue, which was then washed with a small amount of water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropylether and diethyl ether to obtain 1.74 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[CH:38]([C:41]1[S:42][C:43]([C:46]([N:48]2[CH2:53][C:52]3([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:51][CH2:50][CH2:49]2)=[O:47])=[CH:44][N:45]=1)([CH3:40])[CH3:39].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:56]2[CH2:55][CH2:54][C:52]3([O:51][CH2:50][CH2:49][N:48]([C:46]([C:43]4[S:42][C:41]([CH:38]([CH3:40])[CH3:39])=[N:45][CH:44]=4)=[O:47])[CH2:53]3)[CH2:58][CH2:57]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.575 g) in MeCN (3 mL) was added dropwise to a solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.229 g) and triethylamine (0.21 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-8% MeOH in DCM to give the subtitled compound as a yellow solid. Yield 0.395 g.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)=[N+]=[N-].[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH:22]=O>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:26]([O:25][C:21](=[O:24])[CH:22]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(C=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
cis-2-Azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine is treated with zinc dust in 50% aqueous acetic acid as described in Preparation 7. Reaction of the crude reduction product with benzyl glyoxalate in methylene dichloride as described in the procedure of Example 1 gives N-(cis-3-benzyloxycarbonylamino-4-oxo-2-azetidinyl-methyl)iminoacetic acid benzyl ester which, when treated with acetyl chloride according to the procedure of Example 1, gives 3-acetyl-6β-benzyloxycarbonylamino-7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][CH2:21][C@H:22]2[O:29][C@H:26]([O:27][CH3:28])[C@H:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:24]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:23]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:31]([O:30][C@@H:25]1[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:22]([CH2:21][O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:29][C@@H:26]1[O:27][CH3:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.314 g, 2.46 mmol) is dissolved in hot toluene (20 ml) and methanol (80 ml) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D -glucopyranoside as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: COc1cccc(S)c1
Product: COc1cccc(Sc2ccc(F)cc2Br)c1

Procedure:
Prepared from 3-methoxy-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](Cl)=[O:28]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:33])=[C:24]([F:23])[CH:25]=3)([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)c(F)c1
Yield: 79.1 %

Procedure:
Using the method of Example 601, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 770 mg, 2.59 mmol) was reacted with 3,4-difluorobenzoyl chloride (1.14 g, 6.48 mmol). The crude product was purified as described in Example 601 to provide 896 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-3,4-difluorobenzamide as a white solid, mp 165-166° C. MS (APCI) m/z 438 (M+H)+; Anal. Calcd for C24H25F2N5O: C, 65.89; H, 5.76; N, 16.01. Found: C, 65.84; H, 5.58; N, 15.92.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.N[C:11](N)=[O:12].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[OH:12][C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Oc1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a four-necked flask of 1 l capacity were charged 64.8 g (0.6 mol) of o-phenylenediamine, 31.3 g (0.5 mol) of hydrochloric acid, 36.0 g (0.6 mol) of urea and 50 ml of xylene, and a reaction was effected at 140°-150° C. for 5 hours while distilling out 20 ml of water. Then, the reaction product was charged into a four-necked flask of 1 l capacity, into which 30 g (0.75 mol) of sodium hydroxide and 600 ml of water had been previously charged, and the resulting mixture was stirred at 80° C. for 15 hours. Then, thus treated mixture was filtered while it was hot, and the filtrate was cooled to form a precipitate. The resulting precipitate was filtered, and the filter cake was washed with water to obtain the aimed 2-hydroxybenzimidazole having a melting point of 316°-317° C. in an yield of 53.6 g (66.6%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:1]([O:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OC1CCCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC1CCCC1
Reaction time: 8 h

Procedure:
Acryloyl chloride (75 mL) was added to a stirred solution of cyclopentanol (88 g, 1 mol) and triethylamine (175 mL) in dry THF (500 mL) at a rate slow enough to prevent overheating of the reaction. The reaction mixture was allowed to stand overnight, filtered through a pad of Celite, evaporated to an oil, and distilled to give cyclopentyl acrylate as a colorless liquid (bp 74-79/˜60 mm Hg). The structure of the product was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n2)ccc2c1CCC(NCCO)CC2
Yield: 27 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (2,5-dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine were combined to yield 2-(2-{5-Chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol (105.68 mg, 27% yield) as a brown foam. 1H-NMR (CDCl3) δ 9.75 (2s, 1H), 8.65 (dd, J=8.6 8.2 Hz, 1H), 8.15 (s, 1H), 7.96 (m, 2H), 7.58 (m, 1H), 7.48 (s, 1H), 7.23 (m, 1H), 6.82 (d, J=7.7 Hz, 1H), 5.30 (s, 1H), 3.73 (s, 3H), 3.26 (br s, 5H), 2.83 (m, 3H), 2.70 (m, 3H), 2.70 (m, 1H), 2.48 (m, 1H), 2.22 (m, 7H, 1.31 (m, 2H). LC/MS (ESI+)=587 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(C1C=CC=CC=1CC)C>[OH:8][C:7]1[C:2]2=[N:1][CH:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncccc1O
Agent: CCc1ccccc1CC
Product: CCOC(=O)c1cnc2c(O)cccn2c1=O
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Diethylbenzene Process: A mixture of 66.0 g of 2-amino-3-pyridinol, 220.0 g of diethyl ethoxymethylenemalonate, and 1.0 liter of diethylbenzene was heated so that the internal temperature reached 140° in 1 hour, was kept for 1 hour at 140°, then heated so that the temperature rose to 180° in 1 hour, and then kept 1 hour at 180°. During this entire heating period, 50 ml. of distillate was collected. The solution was allowed to cool spontaneously, was cooled at 0°, filtered, and the solid washed with diisopropyl ether to give 130.0 g of product, after drying at 56° in vacuo. The m.p. was 175°-177° and a mixture m.p. with the product isolated in (a) above was 175°-177°. The ir and pmr spectra of the two samples were superimposable. The yield was 93%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.[Mg+2]>>[N:27]1([C:14](=[O:15])[CH:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:8]=2)=[O:11])[C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mg+2]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)N1CCC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and azetidine (CAN 503-29-7) as starting materials and isolated (29 mg, 54%); MS (ESI, m/z): 414.6 (M+H+).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19]O)=[C:15]([CH3:17])[N:16]=1)[CH3:11].[OH-].[Na+]>CCCCCC.O>[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19][O:2][N+:1]([O-:4])=[O:3])=[C:15]([CH3:17])[N:16]=1)[CH3:11]
Reactant: CCc1nc(C)c(CCO)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCc1nc(C)c(CCO[N+](=O)[O-])s1
Reaction time: 2 h
Yield: 58 %

Procedure:
Fifteen (15) ml of nitric acid of (85–90%) were added dropwise to 15 ml of sulfuric acid (95–98%) over a time period of 20 minutes while keeping the temperature at 0–5° C. After 2 hours, 14.3 grams (83.60 mmole) of 2-ethyl-4-methyl-5-thiazoleethanol, prepared as described above, were added, while the temperature was still maintained at 0–5° C., the reaction mixture was stirred for 2 hours at the same temperature, and was then poured carefully onto 125 ml of cold water. The water solution was made basic with a 20% aqueous solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined and dried over sodium sulfate, filtered and evaporated to dryness. Chromatography of the crude product on silica gel (using a mixture of 75:25 ethyl acetate:hexane as an eluent) yielded 10.5 grams (58% yield) of colorless liquid having a purity of 98%, as determined by gas chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][O:12][CH3:13])[CH:10]=1)[C:6]#[N:7])=[O:2].CC(=CC)C.Cl([O-])=[O:20].[Na+]>C(O)(C)(C)C.O>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=1)[C:1]([OH:20])=[O:2])#[N:7]
Reactant: COCc1cc(C#N)cc(C=O)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COCc1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a reaction mixture of 3-formyl-5-methoxymethyl-benzonitrile (128 mg, 0.73 mmol) in tert-butyl alcohol (3 mL) and water (1.5 mL) were added 2-methyl-2-butene (1.5 mL) and sodium chlorite (198 mg, 80% technical grade, dissolved in 1.5 mL of water), respectively. The resulting mixture was stirred at room temperature for 5 h then partitioned between water and methylene chloride. The aqueous layer was extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to dryness to afford 3-cyano-5-methoxymethyl-benzoic acid (90 mg, 64%).