Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[C:29]([F:35])[N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[F:35][C:29]1[N:28]=[C:27]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:32]=[CH:31][C:30]=1[CH2:33][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: Fc1cnc2[nH]ccc2c1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(F)cc34)c(F)n2)cn1
Yield: 8.7 %

Procedure:
In a round bottom flask, 5-fluoro-1H-pyrrolo[2,3-b]pyridine (155, 0.115 g, 0.845 mmol) was combined with (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (156, 0.397 g, 1.10 mmol), 2.60 mL of acetonitrile, trifluoroacetic acid (0.325 mL, 4.22 mmol) and triethylsilane (0.810 mL, 5.07 mmol) and the reaction was heated to reflux for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1622, 28 mg). MS (ESI) [M+H+]+=382.1.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]1([C:22]#[C:23][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cnc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cnc(C#Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a round bottom flask was added 2-bromo-5-formylthiazole (3.83 g, 19.9 mmol, purchased from Frontier Scientific, Inc.), THF (100 mL) and triethylamine (20 mL). To the solution was successively added CuI (228 mg, 1.20 mmol), PdCl2(PPh3)2 (420 mg, 0.60 mmol) and a solution of phenylacetylene (2.24 g, 21.9 mmol) in THF (20 mL) over a period of about 5 minutes. The reaction was then stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, the residue transferred to a 1.0-L separatory funnel with EtOAc (200 mL) and saturated aqueous sodium bicarbonate (300 mL) and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (2×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient ranging from 5% to 50% EtOAc in hexanes to afford the titled compound, 2-phenylethynyl-thiazole-5-carbaldehyde, (3.94 g, 93%) as an orange solid.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[O:9])=[CH:6][C:5]=1[CH3:20].Cl[CH:22]([OH:24])[CH3:23].[CH2:25](O)C>>[CH3:17][CH2:16][CH2:15][CH:11]([NH:10][C:8](=[O:9])[C:7]1[CH:18]=[CH:19][C:4]([O:3][CH2:23][CH2:22][O:24][CH3:25])=[C:5]([CH3:20])[CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(C)c1
Reactant: CCO
Reactant: CC(O)Cl
Agent: [K+]
Agent: [OH-]
Product: CCCC(CCC)NC(=O)c1ccc(OCCOC)c(C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Potassium hydroxide (4 mmol) was dissolved in ethanol (5 mL) and heated at 80° C. 4-hydroxy-3-methyl-N-(1-propyl-butyl)-benzamide (example 58) (1 mmol) was added into the solution followed by chloroethanol (3 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated down and dissolved in 5% citric acid. the mixture was stirred for 1 hour. The aqueous mixture was extracted three times with ethyl acetate. The combined ethyl acetate was washed with water and dried down over sodium sulfate. The organic layer was concentrated down and purified by HPLC to yield 39% of N-(heptan-4-yl)-4-(2-methoxyethoxy)-3-methylbenzamide. MS (M+H, 308.25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH:17]([F:19])[F:18].Cl[C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]2[CH:22]=[C:23]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[N:24]=[N:25][CH:26]=2)=[CH:4][C:3]=1[CH:17]([F:18])[F:19]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(F)F)c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(Cl)c(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=335.3 (M+H+), was prepared from 2-(4-chloro-3-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O.C(OCC)(=O)C.O1CCCC1>[CH3:24][S:25]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 2 h
Yield: 70.6 %

Procedure:
1.4 g of potassium carbonate dissolved in 20 ml of water was added to 1.15 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 40 ml of ethyl acetate and 20 ml of tetrahydrofuran. Then, 0.57 g of methanesulfonyl chloride was added thereto and the mixture was stirred for 2 hours. After the organic layer was collected by separation and dried, the solvent was removed. The resulting crystals were recrystallized from tetrahydrofuran-isopropyl ether to obtain 1.08 g of 2-methylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][O:15][N:16]=[CH:17][C:18]1[CH2:19][NH:20][CH2:21][CH2:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][N:16]=[CH:17][C:18]1[CH2:19][N:20]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:21][CH2:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CON=CC1=CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=CC1=CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.3 %

Procedure:
A solution of 97% 4-nitrophenyl chloroformate (1.5 g, 7.22 mmoles) in dichloromethane (15 mL) was added at 0° C. to a stirred solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (0.92 g, 6.6 mmoles) and triethylamine (0.92 mL, 6.6 mmoles) in dichloromethane (20 mL). The reaction mixture was then stirred at room temperature for 20 minutes, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The solid was recrystallized from benzene-cyclohexane to give 1.9 g (95%) of the desired product with mp 109°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[N:8]=[CH:9][N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1)=[O:6].[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>N1C=CC=CC=1>[CH2:21]([S:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[N:8]=[CH:9][N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])[CH:11]=1)=[O:6])(=[O:25])=[O:24])[CH3:22]
Reactant: CCS(=O)(=O)Cl
Reactant: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc(N)c2)c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C(=O)c2cn(S(=O)(=O)N(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution of Example 55C in pyridine (30 mL) was treated with ethanesulfonyl chloride (0.11 mL, 11 mmol) at 0° C. The mixture was stirred at room temperature for the next 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate)to provide 2.31 g (57%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH2:28])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7].C(N([CH2:36][CH3:37])CC)C.[C:38](Cl)(=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH:28][C:38](=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:36][CH3:37])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Reaction time: 8 h

Procedure:
1.0 g of 3β-amino-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-1) [see Example I] were dissolved in 30 ml dry methylene chloride and treated with 15 ml triethyl amine under stirring. 1.2 g of caproyl chloride acid in 10 ml methylene chloride were added dropwise to the resulting solution, and the stirring was continued overnight. The reaction mixture was poured into water extracted with methylene chloride, the organic fraction was then dried over sodium sulfate, evaporated to dryness and chromatographed over silica gel with a mixture of ethyl acetate and hexane (6:4 and 8:2), to give 0.7 g 3β-caprylamido-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-14).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].Cl>CN(C)C=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
To a mixture of 4-mercaptophenol (3.78 g), potassium carbonate (8.2 g) and N,N-dimethylformamide (40 ml) was added dropwise under ice cooling a solution of N-(2-bromoethyl)phthalimide (7.62 g) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 16 hours and poured into 3% hydrochloric acid (220 ml), and the resulting crystals were collected by filtration and dried to give N-[2-(4-hydroxyphenylthio)ethyl]phthalimide (9.1 g).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[CH3:41][O:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)[CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=3)[S:32][C:33]=2[CH:39]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Product: COc1ccc2nc(N(CCc3ccc(OC(C)(C)C(=O)O)cc3)Cc3ccc(C(F)(F)F)cc3)sc2c1

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and 2-chloro-6-methoxy benzothiazole.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[N:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCc1cc2ccccc2cn1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-isoquinoline was synthesized (79%) from isoquinolin-3-yl-acetonitrile (234, 1.22 g, 7.26 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.64 g, 7.26 mmol) and NaH (Aldrich, 640 mg, 60%, 16.0 mmol) in a similar manner in two steps as described in Example 222.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (2.2 g, 4.67 mmol) and 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (2.82 g, 4.86 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[O:5]1[CH2:6][CH2:7][CH2:8][O:9][CH:4]1[CH2:3][CH2:2][CH:17]([CH:11]1[CH2:12][CH:13]2[CH2:16][CH:10]1[CH:15]=[CH:14]2)[OH:18]
Reactant: O=CC1CC2C=CC1C2
Reactant: BrCCC1OCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)C1CC2C=CC1C2
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A Grignard reagent was customarily prepared from 36.2 g of 2-(2-bromoethyl)-1,3-dioxane in 200 ml of dry tetrahydrofuran. Then 19.5 g of 5-norbornene-2-carbaldehyde was added dropwise over 30 minutes to the Grignard reagent at 20° C. Stirring was continued for 30 minutes whereupon the reaction solution was added to a saturated aqueous solution of ammonium chloride to stop reaction. After diethyl ether extraction, the organic layer was successively washed with water, saturated sodium bicarbonate water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 36.2 g of 3-(1,3-dioxan-2-yl)-1-(5-norbornen-2-yl)-1-propanol (boiling point 125° C./27 Pa, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: COc1cccc(CN)c1
Solvent: C1CCOC1
Product: COc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzylamine (23 g) was dissolved in 150 ml of tetrahydrofuran, and a solution of 32 g of t-butyl dicarbonate in tetrahydrofuran (50 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and successively washed with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give t-butyl N-(3-methoxybenzyl)carbamate. The resulting t-butyl N-(3-methoxybenzyl)carbamate was then dissolved in 250 ml of acetonitrile, 30 g of N-bromosuccinimide was added thereto under ice-cooling, the mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by a silica gel column, to give 36 g of the title compound in the 2:1 hexane-diethyl ether fraction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([O:10]C)[CH:3]=1.[Br:12]Br.[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([OH:8])[C:4](=[CH:3][C:2]=1[CH3:1])[OH:10]
Reactant: COc1ccc(C)cc1OC
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(O)cc1Br

Procedure:
To a solution of homoveratrole (136.4 g, 1.1 mol) in chloroform (1.2 L) and dichloromethane (300 mL) was slowly added a solution of bromine (66 mL, 1.28 mol, 1.2 eq.) in carbon tetrachloride (250 mL). After 5 hours the reaction mixture was neutralized to pH7 with an aqueous solution of sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was dried over sodium sulfate, filtered, and the volatiles were removed in vacuo, affording the title compound as a light brown solid, m.p.: 92-98° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].O1CC[CH2:28][CH2:27]1>>[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([N:1]([CH2:23][CH3:24])[CH2:27][CH3:28])[CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCI
Reactant: C1CCOC1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(CC)[C@H]1CCN(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 1.40 g of (S)-3-amino-1-(benzyloxycarbonyl)pyrrolidine (J. Med. Chem., 1992, 35, 1764-1773) in 28 ml of tetrahydrofuran, 2.6 g of potassium carbonate and 1.0 ml of ethyl iodide were added under ice-cool stirring, followed by stirring for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with water, followed by extraction with ethyl acetate, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.70 g of the objective compound as a yellow oily product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O.CO>[CH:23]1([N:20]2[CH2:19][CH2:18][C:17](=[O:28])[N:16]([CH3:29])[C:15]3[C:21]2=[N:22][C:12]([NH:11][C:8]2[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[N:13][CH:14]=3)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)c1coc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3nc(C(=O)O)co3)ncc21
Yield: 60.4 %

Procedure:
Ethyl2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-1,3-oxazole-4-carboxylate (Intermediate 151; 160 mg, 0.40 mmol) was dissolved in THF (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (84 mg, 2.0 mmol) was added and a few drops of methanol and the mixture stirred at room temperature overnight. The mixture was neutralised with 2N HCl(aqu) and concentrated. The residue was taken up in MeOH/Water and absorbed onto an SCX column, washed with methanol/water and eluted with ammonia in methanol. Product containing fractions were concentrated, the residue taken-up in DCM, dried (MgSO4) and concentrated to give the title compound as a white solid (90 mg, 60%).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.[CH:28]1([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[CH2:30][CH2:29]1>C(O)C>[CH:28]1([N:31]2[CH2:36][CH2:35][C:34]3[N:8]([CH2:18][CH2:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]4[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=4[C:33]=3[CH2:32]2)[CH2:30][CH2:29]1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCN(C2CC2)C1
Yield: 6.1 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol), 2-phenyl ethyl bromide (0.43 ml, 3.1 mmol), triethyl amine (0.43 ml, 3.1 mmol) and N-cyclopropyl-4-piperidone hydrochloride (650 mg, 4.72 mmol) were combined in ethanol (3 ml) to obtain 62 mg of 2-cyclopropyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole after purification on neutral alumina using ethyl acetate-hexane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CCOCC>[CH:9]1([C:15]([C:5]2[NH:4][CH:8]=[CH:7][CH:6]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C1CCCCC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C1CCCCC1
Yield: 18.9 %

Procedure:
To a solution of MeMgBr (99.3 mL, 298 mmol) in Et2O (500 mL) a solution of 1H-pyrrole (20 g, 298 mmol, dissolved in Et2O) was added dropwise at rt under N2. The mixture was heated to reflux for 30 min and cyclohexanecarbonyl chloride (43 g, 298 mmol) was added dropwise at −30° C. The reaction was refluxed for 30 min, quenched by slowly addition of sat. NH4Cl, diluted with EA and water, washed with (3×) water and once with brine. The organic layer was dried over Na2SO4, concentrated and purified by CC to obtain compound 25a (10 g, 20%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH2:23][CH3:24])[CH3:21].C(OC(C)C)(C)C>O>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC1CCCCN1CCCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 54 %

Procedure:
Prepared analogously to Example 2 from 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[2-[(diethylamino)methyl]-piperidin-1-yl]propanamine in a yield of 54% of theory, m.p. 148.0°-149.5° C. (diisopropylether). Soluble in water.