Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:36]([N:38]([C@@H:50]([CH3:58])[CH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:56]([O:55][CH:51]([O:52][CH2:53][CH3:54])[C@@H:50]([N:38]([CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[C:36](=[O:37])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH3:58])[CH3:57]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 84 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:11][F:12])[O:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[C:18]([CH3:23])[C:17]=1[CH3:24]>CS(C)=O>[F:1][CH2:2][C:3]1([CH2:11][F:12])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[C:18]([CH3:23])[C:17]=2[CH3:24])[CH2:7][O:8]1
Reactant: OCC1COC(CF)(CF)OC1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2COC(CF)(CF)OC2)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of the (2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methanol (1.6 g, 8.98 mmol) obtained in the step (7a), sodium hydride, in oil (431 mg, 9.88 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (1.42 g, 8.98 mmol) was added and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (1.63 g, yield: 60.6%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1I.[NH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[NH:16][CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1ccccc1C1CC1CN
Reactant: Clc1c(I)ccn2c(CC3CC3)nnc12
Product: N#Cc1ccccc1C1CC1CNc1ccn2c(CC3CC3)nnc2c1Cl
Yield: 35.3 %

Procedure:
A mixture of 8-chloro-3-(cyclopropyl methyl)-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (60 mg, 0.180 mmol), 2-(2-(aminomethyl)cyclopropyl)benzonitrile (31.0 mg, 0.180 mmol) was reacted in a manner similar to Example 1 to give 2-(2-(((8-chloro-3-(cyclopropylmethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)methyl)cyclopropyl)benzonitrile (24 mg, 32.5%) as a film. 1H NMR (400 MHz, METHANOL-d4) δ 8.15 (d, J=7.5 Hz, 1H), 7.62 (dd, J=7.8, 1.0 Hz, 1H), 7.53 (td, J=7.8, 1.3 Hz, 1H), 7.29 (td, J=7.7, 1.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 3.65 (dd, J=14.6, 6.0 Hz, 1H), 3.51 (dd, J=14.6, 6.5 Hz, 1H), 2.98 (d, J=6.8 Hz, 2H), 2.28-2.20 (m, 1H), 1.55 (ddd, J=8.7, 6.1, 4.8 Hz, 1H), 1.26-1.08 (m, 3H), 0.65-0.54 (m, 2H), 0.36-0.25 (m, 2H). LCMS: M+1=378.0.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round-bottom flask equipped with addition funnel and argon inlet was added 50 mL of aniline III which was stirred mechanically at 0° C. under argon atmosphere. Ethyl bromoacetate, 25 mL (224 mmol) was added in dropwise fashion over 60 min. The mixture slowly solidified and was allowed to stand unstirred at -25° C. for 18 hours. The solid was chipped from the flask and partitioned between dichloromethane (CH2Cl2) and water. The aqueous layer was made basic with 20 mL 50 NaOH solution and extracted with CH2Cl2. The combined organic layers were washed well with H2O, dried over MgSO4 and concentrated. The residue was crystallized from hexane containing a trace of CH2Cl2. Total yield was 28 g (156 mmol, 70% yield) based on ethyl bromoacetate used. mp. 54°-55° C., 1H-NMR (CDCl3) ppm δ7.19 (t, 2H, J= 7 Hz), 6.76 (t, 1H, J=7 Hz), 6.60 (d, 1H, J=7 Hz), 4.24 (q, 2H, J=7 Hz), 3.89 (S, 2H), 1.29 (t, 3H, J=7 Hz; IR (KBr) 3420, 1742, 1610, 1520, 1220 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[I:1])=[CH:7][CH:8]=1)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc2cccc(I)c2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(I)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-iodo-2-naphthol, as described in Step A, (2.75 g, 10.2 mmol) in dry DMF (25 mL), under argon, were added imidazole (1.39 g, 20.4 mmol) and triisopropylsilyl chloride (2.55 g, 13.2 mmol). The resulting mixture was stirred at ambient temperature for 4 hrs, then quenched with 10% aqueous citric acid (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-50% hexane to yield the desired product as a white solid.
Reaction SMILES: [C:1]([CH:6]([CH:9]=O)[CH:7]=O)([O:3][CH2:4][CH3:5])=[O:2].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:9]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=[N:20]2)=[CH:15][CH:14]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C=O)C=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1
Yield: 48.9 %

Procedure:
A solution of carbethoxymalonaldehyde (0.8 g, 5.55 mmol; obtained according to Panizzi, L. Gazz.Chim.Ital., 1946, 76, 56) in ethanol (25 mL) was treated with 4-chlorophenylhydrazine hydrochloride (1.0 g, 5.55 mmol) at reflux for 5 h. The resulting reddish mixture was concentrated to an oil that was purified by flash chromatography to give ethyl 1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (0.68 g, 49%) as a white solid: mp 127°-128° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.37 (s, 1H, pyrazole), 8.09 (s, 1H, pyrazole), 7.67 (dt, Jt =2, Jd =9, 2H, arom), 7.44 (dt,Jt =2, Jd =9, 2H, arom), 4.35 (q, J=7, 2H, OCH2), 1.38 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H11ClN2O2 : C 57.50; H 4.42; N 11.17. Found: C 57.49; H 4.46; N 11.16.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:23]1([CH2:29][CH2:30]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCO>[C:23]1([CH2:29][CH2:30][NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: COCCO
Product: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c(NCCc3ccccc3)cccc21

Procedure:
15 g of 1,6-dinitroanthraquinone and 45 ml of β-phenylethylamine are stirred at 50° - 55° C (approx. 3 hours being required) until no further starting material is detectable. The mixture is diluted with 45 ml of ethylene glycol monomethyl ether whilst warm and the reaction product which separates out is filtered off at 50° C and rinsed with a little ethylene glycol monomethyl ether and water. 13.6 g of pure 1-β-phenylethylamino-6-nitroanthraquinone are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.Cl.Cl[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:3][S:4][C:5]1[N:9]=[C:8]([N:10]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1
Reactant: ClCCNCCCl
Reactant: CSc1nc(N)n(-c2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCNCC2)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.7 g) was taken in dry DMF (100 ml) and a solution of compound 3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-amine (4 g in 10 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and a solution of bis(2-chloroethyl)amine hydrochloride (4.15 g) in dry DMF (20 ml) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using methanol\dichloromethane (1:9) as eluent to afford 1-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine, G-26-In, as brown oil.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:18]=[C:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: O=C1CCc2cccc(N3CCNCC3)c2N1
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4NC(=O)CC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 450.2 (Exact Mass: 449.24).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]([CH3:12])=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]2=[N:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[CH2:9][CH2:10][C:5]2=[N:4][N:3]([CH3:2])[C:11]([CH3:12])=[C:6]2[CH2:7]1
Reactant: ClCCCBr
Reactant: Cc1c2c(nn1C)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c2c(nn1C)CCN(CCCCl)C2
Yield: 43.2 %

Procedure:
To a mixture of 2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride (2.0 g, 13.22 mmol, 1.0 eq) and K2CO3 (5.47, 39.66 mmol, 3.0 eq) in 40 mL of acetone was added 1-bromo-3-chloropropane (4.16 g, 26.44 mmol, 2.0 eq). The reaction mixture was heated to reflux for 5.0 h and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 100:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (1.3 g, 44.21%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 228.73 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=2)[N:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[C:13]([C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([NH:1][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[N:3]2)[CH:12]=[CH:11][CH:10]=1)([OH:15])=[O:14]
Reactant: NC1=NN(c2cccc(C(=O)O)c2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1=NN(c2cccc(C(=O)O)c2)CC1)Nc1ccccc1

Procedure:
3-Amino-1-(3-carboxyphenyl)-2-pyrazoline (108 mg) and phenylisocyanate (140 mg) in chloroform (10 ml) were heated to reflux overnight. The resultant solid was collected and dried to yield 1-(3-carboxyphenyl)-3-(3-phenylureido)-2-pyrazoline m.p. 255° decomp.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]2O[C@@H:13]32)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[FH:29].[K].CS(C)=O>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([F:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: F
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 140 °C
Yield: 19.9 %

Procedure:
A mixture of 100 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione, 200 mg of potassium hydrogen fluoride and 1 ml of dimethyl sulfoxide was heated at 140° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (50/1)] to give 20 mg of 17α-acetoxy-6-fluoro-2-oxapregna-4,6-diene-3,20-dione.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[Br:29][C:30]1[CH:31]=[C:32]([NH2:37])[C:33]([NH2:36])=[CH:34][CH:35]=1>CN(C=O)C.N1C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]2[NH:36][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:37][C:32]=2[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(Br)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To the mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2 g, 8.7 mmol) in DMF (15 mL) and pyridine (15 mL) was added CDI (1.55 g, 9.57 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 4-Bromo-benzene-1,2-diamine (1.63 g, 8.7 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (10 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 5-Bromo-2-piperidin-4-yl-1H-benzoimidazole (1.47 g, 55%) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29](OS(C)(=O)=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([N:5]2[CH2:6][CH2:7][C:2]([NH:8][C:9]3[C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=5[S:15][C:11]=4[N:12]=[CH:13][N:14]=3)([CH3:1])[CH2:3][CH2:4]2)[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCNCC1
Reactant: CC(OS(C)(=O)=O)c1cccc(F)c1
Product: CC(c1cccc(F)c1)N1CCC(C)(Nc2ncnc3sc4c(c23)CCCC4)CC1

Procedure:
The title compound was prepared (97 mg, 81%) from (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine(150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethyl ester (61.1 mg, 0.28 mmol) by following the procedure described for preparation 12. 1H NMR (400 MHz, CDCl3): 6 (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89–6.79 (m, 3H), 3.91 (q, 1H), 2.80–2.74(m, 4H), 2.20–2.09(M, 2H), 1.90 (m, 2H), 1.89–1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (SEI): m/z: Calculated: 424.2; Observed: 425.2 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+].O>CO>[C:14]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of methyl-indole-6-carboxylate in MeOH (1.7 M) was added cyclohexanone (3.0 eq.) followed by 30% NaOMe in MeOH (6.0 eq.) in 100 ml portions over 20 min. The resulting mixture was stirred at RT for 45 min and refluxed for 8 h. Water was added, and the mixture stirred at RT until all solids had dissolved. The organic solvent was removed under vacuum and the pH of the aqueous phase adjusted to 1, by slow addition of concentrated HCl at 0° C. The precipitate was isolated by filtration, and then washed with water, until the pH of the water reached 6-7. Drying under high, vacuum gave the title compound as a beige solid (100%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.49-1.98 (m, 8H), 6.22 (bs, 1H), 7.50 (s, 1H), 7.64 (d, J 7.6, 1H), 7.75 (d, J 7.6, 1H), 8.02 (s, 1H), 11.39 (s, 1H); MS (ES+) m/z 242 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.O>[CH3:16][O:15][C:13]([CH2:12][NH:11][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)=[O:14]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 50.0 g (0.400 mol) of nicotinic acid, 50.0 g (0.400 mol) of methyl glycinate hydrochloride, 90 g (0.440 mol) of dicyclohexylcarbodiimide, and 2 g of p-toluenesulfonic acid in 500 ml of dry pyridine was stirred overnight at room temperature. Filtration and evaporation in vacuo gave a heavy oil which was dissolved in 500 ml of water. After basification with ammonia the aqueous solution was extracted with 3×300 ml of dichloromethane. The organic phase was dried over magnesium sulphate, and removal of the solvent in vacuo gave crude 77 as a heavy yellow oil. Yield: 63.0 g (0.320 mol, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:26][N:25]=[N:24][N:2]=1
Reactant: N#Cc1ccccc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: 93 °C
Yield: 15.4 %

Procedure:
A mixture of 2-cyanophenyl bromide (1.00 g, 5.49 mmol), dibutyltin oxide (90.4 mg, 0.549 mmol) and trimethylsilyl azide (1.26 g, 10.98 mmol) in toluene (10.9 mL) were heated at 93° C. for 72 hours. The solvent was removed under reduced pressure and chased with methanol. The residue obtained was partitioned between ethyl acetate (25 mL) and 10% sodium bicarbonate solution (25 mL). The organic phase was extracted with an additional aliquot of 10% sodium bicarbonate solution. The combined aqueous extracts were acidified to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (190 mg. 74%) as a white solid. 1H NMR (CD3OD, 300 MHz) δ7.48-7.6 (m, 2H), 7.70 (dd, J=2 Hz, 7 Hz, 1H), 7.84 (dd, J=1 Hz, 6 Hz, 1H). HRMS (DCl/NH3) m/e, calcd for C7H6N479Br: 224.9776, found 224.9762. IR (KBr) 3440, 2600, 1602, 1056, 748 cm-1. Anal calc for C7H6N4Br: C, 37.36; H, 2.24; N, 24.90. Found: C, 37.44; H, 2.25; N, 24.77.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([O:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([NH:33][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:12]#[N:13])=[O:4])[CH2:31][CH2:32]2)=[CH:22][CH:21]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccc(OC2CCC(N)CC2)cc1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 4-(4-aminocyclohexyloxy)-benzoic acid tert-butyl ester (89 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 452 (M+H)+; 1H NMR (CDCl3) δ 7.91 (d, 2H), 6.86 (d, 2H), 4.74 (m, 1H), 4.60 (m, 1H), 4.28 (m, 1H), 3.64 (m, 2H), 2.32-2.59 (m, 6H), 2.17 (m, 2H), 2.04 (m, 2H), 1.24-1.54 (m, 4H).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][N:9]1[C:13]([Br:1])=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)OCCn1cnnn1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCn1nnnc1Br
Yield: 94.7 %

Procedure:
Bromine (69.1 g) in chloroform (80 ml) was added to a stirred refluxing solution of 1H-tetrazole-1-ethanol acetate (ester) (33.8 g) in acetic acid (200 ml) and chloroform (400 ml). After 72 h the mixture was cooled and evaporated, excess, saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate to give the title compound (48.2 g) as a cream solid, m.p. 55°-6° (from diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([NH:34][C:35](=[O:39])[C:36](O)=[O:37])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:35]([NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:39])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)NC(C)(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(tert-butylamino)-2-oxoacetic acid (19 mg, 0.13 mmol). Yield 53 mg (78%).