Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](Cl)=[O:39])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([NH:1][C:2]2[S:3][C:4]3[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:8][CH2:9][C:10]=3[N:11]=2)=[O:39])=[CH:32][CH:31]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccnc1)CC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)Nc2nc3c(s2)CCN(CC=Cc2cccnc2)CC3)cc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 1.0 g (3.5 mmol) of 2-amino-6-(3-(3-pyridyl)allyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine and 0.53 ml (3.8 mmol) of triethylamine in 40 ml of anhydrous chloroform, there is added dropwise at ambient temperature a solution of 3- (4-methoxy-phenyl)-propionyl chloride (bp: 150° C./15 torr) in 7 ml of chloroform. The mixture is stirred for 3 hours at 60°-70° C., cooled and extracted with water. The dried and filtered chloroform solution is evaporated down in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=5:1). Yield: 0.74 g (47% of theory), Melting point: 168°-170° C. (ether).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:24])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C@H:18]3[O:22][C:21](=[O:23])[NH:20][CH2:19]3)=[CH:17][C:11]=2[CH2:10][O:9]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]>CN(C=O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:20]1[CH2:19][C@@H:18]([C:16]2[CH:15]=[CH:14][C:12]3[O:13][C:8]([CH3:24])([CH3:7])[O:9][CH2:10][C:11]=3[CH:17]=2)[O:22][C:21]1=[O:23]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)-LC RT=6.8 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:31])=[C:7]([C:22]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:23])[C:8]([I:21])=[C:9]([C:19]=1[I:20])[C:10]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])=[O:11])(=[O:3])[CH3:2].[OH-:32].[K+].B(O)(O)O.[O:38]1[CH2:40][CH:39]1[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]1[CH2:47][O:46]1>CO.O>[OH:38][CH:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]([OH:46])[CH2:47][N:4]([C:5]1[C:19]([I:20])=[C:9]([C:10]([N:12]([CH2:13][CH2:14][OH:15])[CH2:16][CH2:17][OH:18])=[O:11])[C:8]([I:21])=[C:7]([C:6]=1[I:31])[C:22]([N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])=[O:23])[C:1](=[O:32])[CH3:2])[CH2:40][N:4]([C:5]1[C:19]([I:20])=[C:9]([C:10]([N:12]([CH2:13][CH2:14][OH:15])[CH2:16][CH2:17][OH:18])=[O:11])[C:8]([I:21])=[C:7]([C:6]=1[I:31])[C:22]([N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])=[O:23])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Reactant: C(CCC1CO1)CC1CO1
Reactant: [OH-]
Agent: OB(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CCCCC(O)CN(C(C)=O)c1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I)c1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Acetylamino-N,N,N′,N′-tetrakis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthalamide (5 g, 6.45 mmol) was added to a stirring solution of potassium hydroxide (0.54 g, 6.5 mmol) in a mixture of methanol (3.5 ml) and water (3.5 ml). To the clear and slightly yellow solution which was obtained was added boric acid (0.35 g, 5.6 mmol). The pH was continuously maintained at pH 12.6 by addition of potassium hydroxide (10 M) and then 2-(4-oxiran-2-ylbutyl)oxirane (0.32 g, 2.24 mmol) was added. The pH of the solution was continuously maintained within the interval 12 and 13 by addition of solid boric acid for 5 hours. And the mixture stirred at ambient temperature overnight (20 hours). LC-MS investigation showed formation of the expected product. Using 18.5 M HCl (50%), the mixture was made acidic, pH 3.5-4.5 and stirred overnight again. Precipitation of unreacted monomer had occurred and removed by filtration of the mixture (funnel sinter 3) and the filter cake washed with water (2×5 ml). The filtrate was then treated with ion exchangers (AMB200C, 9 ml) and (IRA-67, 10 ml). The resins were removed by filtration and rinsed with water and the combined aqueous volume was reduced in vacuo. The crude product was purified by preparative HPLC (column Phenomenex Luna C18 (2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 0-10% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm). After freeze-drying, 869 mg of the title product (47%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C1C=CC=CC=1>[Cl:23][C:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:22]
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCCOCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 12.9 g. (62 mmoles) of tetraethylene glycol monomethyl ether and 4.9 g. (62 mmoles) of pyridine is added dropwise to 77 ml. (124 mmoles) of a 17.2% solution of phosgene in benzene stirred in an ice bath with protection from moisture. The pyridine hydrochloride precipitates during the 35 to 40 minute addition and stirring is continued in the ice bath for an additional 2 hours. The reaction mixture is allowed to warm to room temperature and stirred overnight. The benzene solution is decanted from the pyridine hydrochloride which is washed with additional benzene. A stream of nitrogen is passed through the solution to remove excess phosgene as well as most of the benzene. The residual oil is dissolved in benzene-hexane and filtered to remove additional pyridine hydrochloride. The filtrate is evaporated to dryness in vacuo affording 17.1 g. of a residual oil, the infrared analysis of which reveals a strong carbonyl absorption and minimal hydroxyl absorption. The oil is used as is in the next step.
Reaction SMILES: C(O)(=O)C.[N:5]1([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:18]=[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[C:11]1[N:5]1[CH2:6][CH2:7][N:8]([CH2:20][C:21]#[N:22])[CH2:9][CH2:10]1
Reactant: N#CCCl
Reactant: O=c1cccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: N#CCN1CCN(c2cccccc2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.7 %

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one acetate (10.0 g, described in Example 2), chloroacetonitrile (13.2 g) and potassium carbonate (14.5 g) in acetonitrile (110 ml) was stirred at room temperature for 16 hr, and filtered. The filtrate was evaporated. The residue was chromatographed on silica gel (300 g) using ethyl acetate-acetone (4:1) give 1.9 g of the title compound, which was then crystallized from acetone-diethyl ether: mp 133°-135° C.; ir(CHCl3) 2230 and 1565 cm-1 ; uv max(MeOH) 350 (ε=9810), 254 (ε=14575) and 222 nm(ε=11960); nmr(CDCl3) δ2.75 (t, 4H), 3.4 (t, 4H), 3.55 (s, 2H) and 7.0 (m, 5H); and Anal. Calcd for C13H15N3O: C, 68.4% H, 6.56% N, 18.38% and Found: C, 68.15% H, 6.68% N, 18.25%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=1[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[Cl:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCCCOc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (117 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-chlorophenoxy)-1-propanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 58%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12]2[N:18]([CH3:31])[C:19](=[O:30])[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])=[CH:21][C:11]3=2)[N:7]=1.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[C:19](=[O:30])[N:18]([CH3:31])[C:12]2[N:13]([CH3:17])[C:14]3[C:10]([C:11]=2[CH:21]=1)=[CH:9][C:8]([C:6]1[N:7]=[C:3]([CH2:2][NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[S:4][CH:5]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CCl)n4)ccc3n(C)c21
Reactant: NCCN1CCOCC1
Product: Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNCCN5CCOCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 122 above, with the compound A: 6-(2-chloromethylthiazol-4-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and aminoethylmorpholine.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].[CH3:22][NH2:23]>C(O)C>[ClH:1].[CH3:22][NH:23][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN
Reactant: O=C(CCl)Nc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCO
Product: CNCC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Product: Cl

Procedure:
A mixture of 3.0 g of 2-chloro-4'-(p-nitrophenylthio)acetanilide and a 4.0% aqueous solution of methylamine in ethanol was refluxed for 4 hours. The solvent was evaporated, the residue dissolved on dichloromethane and crystallized by the addition of hexane, giving 2.25 g of the desired product, mp 86°-89° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18](Br)=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37](B(O)O)=[CH:38][CH:39]=[CH:40][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:37]=[CH:38][CH:39]=[C:40]([C:18]2[C:19]3[C:24]([C:11]([C:8]4[CH:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2]([C:26]6[CH:35]=[CH:34][C:33]7[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=7)[CH:27]=6)=[CH:1]5)=[CH:6][CH:7]=4)=[C:12]4[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:41]=1
Reactant: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cccc(-c3c4ccccc4c(-c4ccc5ccc(-c6ccc7ccccc7c6)cc5c4)c4ccccc34)c2)cc1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
Under the nitrogen atmosphere, ([9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (2.0 g) as the tenth intermediate compound, m-biphenylboronic acid (1.4 g), Pd(PPh3)4] (0.1 g), potassium phosphate (1.7 g), and a mixture solvent (16 ml) of toluene and ethanol (toluene/ethanol=4/1 (volume ratio)) were added to a flask and refluxed for 10 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with water. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol, and washed further with ethyl acetate. The obtained crude product was purified by silica gel column chromatography (solvent: chlorobenzene). Finally, after re-crystallization with chlorobenzene, 9-([1,1′-biphenyl]-3-yl)-10-([2,2′-binaphthalen]-7-yl)anthracene (0.5 g) was obtained as the target compound represented by Formula (1-160). The scheme is shown in the following “Reaction 16”.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14]N[C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20].O>CO>[C:23]([CH:21]([CH:19]([C:18]([OH:27])=[O:26])[OH:20])[OH:22])([OH:25])=[O:24].[CH3:8][C:7]1([CH3:17])[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:17]=[CH:16][C:10]=2[CH:11]([C:12]2[CH:23]=[CH:21][CH:19]=[CH:14][CH:13]=2)[CH2:3][CH2:2][NH:1]1
Reactant: C1=CNc2cc(N3CCOCC3)ccc2C=C1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: O
Product: CC1(C)NCCC(c2ccccc2)c2ccc(N3CCOCC3)cc21
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 197.1 %

Procedure:
To a solution of the (+)-8-morpholinylbenzazepine (16 mg, 0.049 mmol) form step H above in methanol (1 mL) was added L-tartaric acid (7.3 mg, 0.049 mmol). After the mixture was stirred at room temperature for 10 minutes, water (20 mL) was added. The resulting solution was lyophilized overnight to give (+)-4-(1,1-dimethyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)morpholine, tartrate salt (23.5 mg, 99%, AUC HPLC 98.9%) as an white solid: 1H NMR (CD3OD, 500 MHz) δ 7.42-7.24 (m, 5H), 7.07 (s, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.56 (d, J=8.7 Hz, 1H), 4.56 (d, J=10.9 Hz, 1H), 4.39 (s, 2H), 3.81 (t, J=4.7 Hz, 4H), 3.63 (br, 1H), 3.35 (br, 1H), 3.31 (s, 3H), 3.11 (t, J=4.7 Hz, 4H), 2.45 (br, 1H), 2.35 (br, 1H), 1.89 (s, 3H), 1.85 (s, 3H); ESI MS m/z 337 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].C[O:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11](=[O:10])[CH2:6][C:7]#[N:8])=[CH:14][C:15]=1[O:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: COCCOc1cc(CC(=O)OC)ccc1OC
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(CC(=O)CC#N)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.9 %

Procedure:
To a 250 mL three-necked round-bottomed flask was added 10 mL of anhydrous THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 8.06 mL, 12.9 mmol) was added and the mixture was stirred for 5 min. Anhydrous CH3CN (0.696 mL, 13.3 mmol) in 5 mL of anhydrous THF was added dropwise at −78° C. After 1 h of stirring, 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester (1.10 g, 4.3 mmol) in 10 mL of anhydrous THF was added dropwise to the resulting white colloidal mixture. The reaction mixture was stirred for an additional 2 h, followed by the addition of saturated NH4Cl solution at −78° C. The solution was warmed to r.t., diluted with 100 mL water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with gradient 30-60% EtOAc in hexanes to yield 769 mg (68% yield) of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyronitrile as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([Cl:14])(=O)C>CO>[ClH:14].[CH3:11][O:9][C:8]([C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: CC(=O)Cl
Reactant: NC1(C(=O)O)CCCCC1
Solvent: CO
Product: COC(=O)C1(N)CCCCC1
Product: Cl
Reaction time: 18 h

Procedure:
1-Aminocyclohexanecarboxylic acid (1.00 g, 6.98 mmol) was added to a solution of acetyl chloride (0.60 mL, 8.44 mmol) in methanol (10 mL). The reaction mixture was allowed to stir for 18 h and then concentrated under reduced pressure. 1H NMR (400 MHz, CD3OD) δ 1.42-1.82 (m, 8H), 2.08-2.20 (m, 2H), 3.82 (s, 3).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH3:19])[C:13]2=[O:18]>C1COCC1.C(O)C>[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH3:19])[CH:13]2[OH:18]
Reactant: CC1Cc2c(cccc2-c2ccccc2-c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1Cc2c(-c3ccccc3-c3ccccc3)cccc2C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
Sodium borohydride (2.34 g, 61.76 mmol, 1.5 equiv) was added in portions to a cold solution (0° C.) of compound 17 (12.27 g, 41.17 mmol, 1.0 equiv) in THF (125 mL) and ethanol (125 mL). The reaction mixture was stirred at room temperature for 2 hours when LC/MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL). 1 M HCl was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 18 (13.0 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1.Br[CH:17]1[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:17]1([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]2)[CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: BrC1CCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C2CCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a suspension of sodium hydride (60% in mineral, 817 mg, 20.4 mmol) in N,N-dimethylformamide (30 mL) was added a solution of methyl 1H-indazole-3-carboxylate in N,N-dimethylformamide (20 mL) at room temperature. After stirring for 30 min, bromocyclobutane (3.45 g, 25.5 mmol) was added, and the mixture was stirred at 90° C. for 13 h. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogencarbonate solution (200 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 200 mL×2). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:6 then 1:5) to give 2.21 g (56%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH2:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:19][C:20]3[CH2:28][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: ClCC1=Cc2ccccc2C1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CC1=Cc3ccccc3C1)CC2
Yield: 4 %

Procedure:
Prepared from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-chloromethyl-1H-indene (prepared from 1H-indene, paraformaldehyde and concentrated hydrochloric acid) in anhydrous dimethylformamide for 2 hours at 50° C. Yield: 4% of theory, Melting point: 134°-138° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45](O)=[O:46])[CH:40]=2)[CH2:35][CH2:34]1.[N+:48]([C:51]1[CH:59]=[CH:58][CH:57]=[C:56]2[C:52]=1[CH2:53][CH2:54][NH:55]2)([O-:50])=[O:49].C(N(CC)CC)C>CN(C=O)C.O>[N+:48]([C:51]1[CH:59]=[CH:58][CH:57]=[C:56]2[C:52]=1[CH2:53][CH2:54][N:55]2[C:45]([C:41]1[N:42]=[CH:43][N:44]=[C:39]([N:36]2[CH2:37][CH2:38][CH:33]([N:25]3[C:26]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[NH:32][C:24]3=[O:23])[CH2:34][CH2:35]2)[CH:40]=1)=[O:46])([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1cccc2c1CCN2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.470 mmol) TBTU were added to 150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 75 mg (0.46 mmol) 4-nitro-2,3-dihydro-1H-indole, 100 μL (0.712 mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto 30 mL water. The aqueous phase was extracted with DCM (3×20 mL). The combined organic phases were dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was dissolved in 3 mL DMF, filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[ClH:11].[CH3:12][N:13]([CH2:15][C:16](Cl)=[O:17])[CH3:14]>>[Cl:11][N:8]1[C:6]2=[N:7][CH:2]=[CH:3][CH:4]=[C:5]2[C:10]([C:16](=[O:17])[CH2:15][N:13]([CH3:14])[CH3:12])=[CH:9]1
Reactant: Cl
Reactant: CN(C)CC(=O)Cl
Reactant: Clc1ccc2cc[nH]c2n1
Product: CN(C)CC(=O)c1cn(Cl)c2ncccc12

Procedure:
The title compound was prepared from 6-chloro-1H-pyrrolo[2,3-b]pyridine (Synthesis, 992, 7, 661-663) and dimethylaminoacetyl chloride hydrochloride (Arch. Pharm. 991, 324, 433-437) in a procedure similar to Example 1. NMR (D6DMSO) δ8 12.65 (s, 1H), 8.60 (s, 1H), 7.95 (d, 1H), 7.32 (d, 1H), 3.60 (s, 2H), 2.22 (s, 3H). 13C NMR (D6DMSO) 195.6, 147.5, 144.4, 134.8, 132.7, 118.0, 116.8, 114.0, 65.9, 45,4 (2). Mass spectrum: 237,239 (P+1, P+3).