Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].O.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([N:4]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCNCC(=O)O
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC(=O)O)c1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
(a-1) To a stirred solution of 1.4 parts of ethyl glycine hydrochloride in 10 parts of water was added a solution of 1.7 parts of 4-fluoro-3-nitrobenzaldehyde in 8 parts of ethanol. Then there were added 1.76 parts of sodium hydrogen carbonate and stirring at room temperature was continued for 48 hours. The precipitated product was filtered off, washed successively with water, ethanol and 2,2'-oxybispropane, and dried, yielding 2 parts (79%) of ethyl N-(4-formyl-2-nitrophenyl)-glycine; mp. 90° C. (int. 29).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])#[N:27]>CN(C=O)C>[C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:31])#[N:27]
Reactant: N#Cc1ccccc1C(=O)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C#N)c1
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a solution of the product of Example 2, Step A (250 mg, 0.82 mmol) in 3 mL of DMF was added 60% NaH (39 mg, 1 mmol, 1.2 eq). After stirring for 5 minutes, 2-cyanobenzoyl chloride (204 mg, 1.23 mmol, 1.5 eq) was added to the reaction mixture. The resultant solution was stirred for 16 hours and the DMF removed in vacuo. The resultant oil was flash chromatographed with 2:1 hexane/ethyl acetate to yield the titled compound (292 mg, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][C@@H:14]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[CH:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][C@@H:14]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[CH:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)CNC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By using tert-butyloxycarbonylglycine (522 mg, 2.98 mmol) and 3α-aminocholestane (1.16 g, 2.99 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (1.65 g, quantitative).
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[O:24]([CH2:31][CH2:32][NH2:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[O:24]([CH2:31][CH2:32][NH:33][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCOc1ccccc1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCCOc2ccccc2)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.6 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 685 mg. of phenoxyethylamine in 15 ml. of benzene is allowed to stir overnight at room temperature. The reaction is concentrated to an oil and partitioned between 50 ml. of chloroform and 50 ml. of 1N aqueous sodium hdyroxide. The chloroform layer is separated, dried over magnesium sulfate and concentrated to give 1.9 g. of the desired product as a foam.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:13])[CH:10]=[N+]=[N-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].O1CCOCC1>CCOCC>[Cl:22][CH2:10][C:9](=[O:13])[C@@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)CCl

Procedure:
To a solution of the crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (7 g, ˜65% pure) in anhydrous ether (150 mL) at 0° C. was added dropwise a solution of 3.65 N HCl in dioxane (4.1 mL, 0.015 mmol). The mixture was stirred until tlc showed the starting material had been consumed. Satd aq NaHCO3 was added and the organic layer was separated, washed with satd aq NaHCO3 and brine, and concentrated to afford a solution of crude (S)-tert-butyl 4-chloro-1-cyclohexyl-3-oxobutan-2-ylcarbamate (5.8 g), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:12]([CH3:28])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:29]>C(O)C.[Ni]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]([CH3:28])[CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:18][CH2:19]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:29]
Reactant: COc1ccccc1N1CCN(CC(C)=Cc2ccc3c(c2)oc(=O)n3C)CC1
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(C)Cc2ccc3c(c2)oc(=O)n3C)CC1
Temperature: 25 °C

Procedure:
0.01 mole of 3-methyl-6-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-1-propenyl}benzoxazolinone is dissolved in absolute ethanol in a 500-cm3 flask equipped with a three-way tap and a magnetic stirrer. 0.5 g of Raney nickel is added and the mixture is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure. After the theoretical amount of hydrogen has been absorbed, the reaction medium is filtered, the filtrate is evaporated to dryness on a water bath under vacuum and the residue is recrystallized in cyclohexane.
Reaction SMILES: [C:1]([O:6][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9]([OH:11])=O)(=[O:5])[CH2:2][CH2:3][CH3:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:38][CH2:39][C:40]([NH:42][C@H:43]([C:46]([OH:48])=[O:47])[CH2:44][OH:45])=[O:41].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:6][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9]([NH:38][CH2:39][C:40]([NH:42][C@H:43]([C:46]([OH:48])=[O:47])[CH2:44][OH:45])=[O:41])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCC(=O)OC(CCC)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC(=O)OC(CCC)CC(=O)NCC(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C

Procedure:
3-Butanoyloxyhexanoic acid (234 mg) prepared by the method described in Preparation 6-(2) and N-hydroxysuccinimide (133 mg) was dissolved in dioxane (3 ml). N,N'-Dicyclohexylcarbodiimide (239 mg) was added thereto under ice cooling. The mixture was reached to room temperature and stirred at ambient temperature over night. The crystallized N,N'-dicyclohexyl urea was filtered off and the filtrate was concentrated to give a residue which was dissolved in N,N-dimethylformamide (5 ml). To this solution was added a solution of N-glycyl-L-serine (324 mg) and triethylamine (280 μl) in water (3 ml) at 0° C. The resulting mixture was reached to room temperature and stirred at ambient temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was subjected to preparative thin layer chromatography (Merck, 0.25 mm×5) and eluted with a mixture of benzene, dioxane and acetic acid (10:5:1). The band containing the object compound was extracted with a mixture of methanol and chloroform (3:7) and the solvent was evaporated off under reduced pressure to afford a wax of N-[N-(3-butanoyloxyhexanoyl)glycyl]-L-serine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccccc1-c1cccc(Br)c1
Reactant: CC(C)(C)c1cccc(C(=O)c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 3′-bromo-2-methoxybiphenyl (1 g, 3.8 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (1.6 mL, 4 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr. A solution of (2-(benzyloxy)-3-tert-butylphenyl)(phenyl)methanone (1.3 g, 3.8 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. The reaction mixture was allowed to reach room temperature slowly and was poured onto saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (3.5 L). Pure 29 (1.2 g, 60%) was isolated.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:16]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:28][N:29]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: O=C(O)c1oc(-c2ccccc2)nc1C(F)(F)F
Product: COCCN(C)c1ncc(NC(=O)c2oc(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N-(2-Methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H18F3N5O3 (m/e) 421, obsd 422 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:13]([CH2:16][CH:17]=O)(=[O:15])[CH3:14]>>[C:13]([C:16]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[NH:1][CH:17]=1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C(N)C#N)cc1
Reactant: CC(=O)CC=O
Product: COc1ccc(-c2[nH]cc(C(C)=O)c2N)cc1

Procedure:
Starting from 2-amino-2-(p-methoxyphenyl)acetonitrile and acetylacetaldehyde, the open-chain intermediate product is prepared, boiling at 180° C./0.03 mm hg. Overall yield of the title compound: 44%, m.p. 198°-200° C. (from diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.Br[C:39]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:40]=1[F:47].N1(CCOC2C=CC(C=O)=CC=2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:39]1[C:40]([F:47])=[CH:41][CH:42]=[C:43]([F:46])[C:44]=1[F:45])[CH:7]=[CH:6]2
Reactant: Fc1ccc(F)c(Br)c1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: O=Cc1ccc(OCCN2CCCCC2)cc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)ccc(F)c3F)ccc2c1
Yield: 45.1 %

Procedure:
Couple trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.81 g, 3.37 mmol) with 2-bromo-1,3,4-trifluoro-benzene (1.42 g, 6.75 mmol) in a procedure similar to the preparation of 6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 0.79 g (45%) of the title compound: mass spectrum (ion spray) m/z=520.3 (M+H).
Reaction SMILES: [CH2:1]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][C:10](=O)[CH2:9][C:7](=O)[NH:6][CH2:5][CH2:4][NH:3][CH2:2]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[NH:3]1[CH2:2][CH2:1][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:10][CH2:9][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=C1CC(=O)NCCNCCCNCCN1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: C1CNCCNCCCNCCNC1

Procedure:
bisacylating 1,3-diaminopropane by reacting it with 2 equivalents of chloroacetyl chloride in the presence of an alkali metal carbonate and a chlorinated aliphatic hydrocarbon at a temperature of from 0° to 30° C. for a period of between 90 minutes and 4 hours to obtain the dichlorodiamide compound of formula I ##STR5## 2) cyclizing the dichlorodiamide compound prepared in the first step by reacting it with an quivalent amount of 1,3-diaminopropane in the presence of an alkali metal carbonate and acetonitrile at a temperature of from 78° to 83° C. for a period of between 20 and 30 hours to obtain dioxocyclam of formula II ##STR6## 3) reducing the dioxocyclam compound prepared in the second step by reacting it with sodium bis(2-methoxy-ethoxy) aluminum hydride in the presence of an aromatic hydrocarbon at a temperature of from 20° to 35° C. for a period of between 90 minutes and 4 hours to obtain 1,4,8,11-tetraazacyclotetradecane of formula III ##STR7##
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.C[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)CN.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:23][C:24]1[CH:25]=[CH:26][C:29]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:30][CH:31]=1
Reactant: COc1cccc(CN)c1
Reactant: COc1cccc(CN2C(=O)CNc3ncc(Br)nc32)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2C(=O)CNc3ncc(-c4ccc(O)cc4)nc32)c1
Yield: 20 %

Procedure:
7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Methyl 2-(3,5-dibromopyrazin-2-ylamino) acetate (0.58 g, 1.8 mmol), 3-methoxybenzylamine (227 μL, 1.8 mmol), diisopropylethylamine (1 mL), and dimethylsulfoxide (1 mL) were heated to 100° C. for 3 d under nitrogen. The reaction was extracted with ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column (0-100% ethyl acetate in hexanes) to give the title compound (124 mg, 20% yield) as a pink solid. MS (ESI) m/z 349.0 [M+1]+.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:14]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@@H:25]1[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:26](=[O:27])[C@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[CH3:13]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(OCC)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 72.3 %

Procedure:
L-prolinal diethyl acetal hydrochloride (726 mg) and benzyloxycarbonyl-D-proline (801 mg, 3.22 mmol) are used to prepare 942 mg (73%) of the title compound as a pale yellow syrup in a manner similar to that as mentioned in Example 8.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([I:16])[CH:10]=1.[ClH:17]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([Cl:17])=[C:11]([I:16])[CH:10]=1
Reactant: Cl
Reactant: Nc1ccc(Br)cc1I
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1ccc(Br)cc1I
Temperature: 60 °C

Procedure:
tert-Butyl nitrite (11.1 ml, 93.3 mmol) is added to a suspension of copper(II) chloride (10.04 g, 75 mmol) in acetonitrile (224 ml) and the mixture is heated with stirring to 60° C. A solution of 4-bromo-2-iodoaniline (18.54 g, 62 mmol) in acetonitrile (56 ml) is added dropwise over about an hour, and once the addition is complete the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to room temperature, poured into 20% aqueous hydrochloric acid (1.3 liters) and extracted with diethyl ether (1.5 liters). The organic extract is separated and the aqueous re-extracted with ether (1 liter). The organic extracts are combined and dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 4-bromo-1-chloro-2-iodobenzene (8.62 g) as an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[O:40]=[C:41]1[NH:45][N:44]=[C:43]([C:46]2[CH:47]=[C:48]3[C:58](=[CH:59][CH:60]=2)[O:57][C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][C:49]3=[O:61])[NH:42]1>CN(C=O)C.O.CCN(CC)CC>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([N:54]4[CH2:55][CH2:56][C:51]5([CH2:50][C:49](=[O:61])[C:48]6[C:58](=[CH:59][CH:60]=[C:46]([C:43]7[NH:42][C:41](=[O:40])[NH:45][N:44]=7)[CH:47]=6)[O:57]5)[CH2:52][CH2:53]4)=[O:36])[CH:32]=3)[CH:27]=[CH:26]2)[CH2:23][CH2:24]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3n[nH]c(=O)[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4n[nH]c(=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Et3N (209 uL), HOBT (91.2 mg) and WSC (115 mg) were added to a suspension of 1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid (116 mg) and 6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (202 mg) in DMF (3 mL), and the mixture was stirred overnight at 50° C. Water was added to the reaction mixture, and the formed solid was collected by filtration. The solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain the intended compound as colorless foam. 1H-NMR (400 MHz, DMSO-d6) δ: 8.06 (1H, d, J=2.3 Hz), 8.00 (1H, dd, J=8.7, 2.3 Hz), 7.29 (1H, d, J=3.2 Hz), 7.26 (1H, d, J=8.7 Hz), 7.24-7.21 (3H, m), 6.58 (1H, d, J=1.0 Hz), 6.40 (1H, dd, J=3.2, 1.0 Hz), 4.44-4.08 (1H, br m), 3.87 (3H, s), 3.80-3.25 (4H, m), 2.97 (2H, s), 2.10-1.70 (4H, m), 1.09-1.01 (2H, m), 0.96-0.89 (2H, m); MS [M+H]+=514.
Reaction SMILES: O=[C:2]([C:13]1[S:17][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:13]2[S:17][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)CCCCc1ccc(C(=O)CCCCc2ccccc2)s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(O)CCCCc1ccc(CCCCCc2ccccc2)s1

Procedure:
This compound is prepared analogously to Example 1b from: 15 g of methyl 5-[5-(1-oxo-5-phenylpentyl)-thien-2-yl]-valerate, 7.6 g of potassium hydroxide, 100 ml of triethylene glycol and 5 g of hydrazine hydrate.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH3:17][O:18][N:19]=[CH:20][CH3:21].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:17][O:18][N:19]1[CH:20]([CH3:21])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16]
Reactant: CC=NOC
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Agent: CON1C(=O)CCCCCCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclododecanone (2.00 g, 9.02 mmol), acetaldehyde O-methyl oxime (0.99 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (2.33 g, 88% yield). Mixture of E/Z isomers in a ratio of 3:1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=2[CH2:24][NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2CN)CC1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution 4-(2-cyano-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.42 mmol) in NH3/EtOH (2M, 10 mL) was added Raney Nickel (3 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 30 min. After this time the mixture was filtered through celite and concentrated to yield the title compound (148 mg). m/z (M+1) 360.23.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[NH:27][CH:26]=1>>[NH:22]1[C:21]2[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]3[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[CH:5][C:4]=2[N:1]=[C:34]1[C:32]1[CH:31]=[CH:30][C:29]2[NH:25][CH:26]=[N:27][C:28]=2[CH:33]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc2nc[nH]c2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5[nH]cnc5c4)nc3c2)cc1

Procedure:
Compound 187 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzimidazole-5-carboxaldehyde. [M+H]+ calcd for C23H20N6O: 397.17; found: 397.52.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH:10]([Mg]Br)=[CH2:11]>C1COCC1>[NH:1]1[C:4]2[C:9](=[CH:8][CH:7]=[N:6][CH:5]=2)[CH:11]=[CH:10]1
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1
Solvent: C1CCOC1
Product: c1cc2cc[nH]c2cn1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 3-nitropyridine in THF at −78° C. is treated with vinyl magnesium bromide (3 eq), stirred at −20° C. for 8 h and quenched with 20% ammonium chloride. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase and the combined extracts are mixed together, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed over silica gel to afford the title 6-azaindole.