Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)C>[C:8]([C:7]1[C:2]([NH:20][CH2:19][CH2:17][OH:18])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Reactant: NCCO
Solvent: CCO
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1NCCO

Procedure:
5 g 2-Chloro-3-cyano-5,4'-bipyridine-1'-oxide and 8 ml ethanolamine are refluxed in 50 ml ethanol for 4 hours and then concentrated under vacuum. The residue is taken up in water, filtered off with suction, washed with water, dried at 110° C. and crystallized from ethanol/glacial acetic acid with addition of activated charcoal. Yield: 4.5 g (81.3% of the theoretical yield), with a melting point of 229° C.-231° C.
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=O)[CH2:2][CH3:3].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)(=[O:21])[CH3:20]>>[CH3:34][C:24]1[CH:23]=[C:22]([C:19](=[O:21])[CH:20]=[CH:17][C:5]2[S:6][C:7]3[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=3[C:4]=2[CH2:1][CH2:2][CH3:3])[CH:27]=[CH:26][C:25]=1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CCCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Product: CCCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from the above-mentioned 3-propyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (112 mg, 0.411 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (90 mg, 0.41 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (107 mg, yield 55%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]([C:21]([F:20])([F:34])[F:33])[CH:23]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[(S)-1-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester (5 g, 18.8 mmol) and 3,5-bis(trifluoromethyl)bromobenzene (4.04 mL, 23.5 mmol) were dissolved in THF (20 mL). The solution was degassed with N2 for 5 minutes, and then cooled to 0° C. Isopropylmagnesium chloride (2M in THF; 23.5 mL, 46.9 mmol) was added slowly, and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. 1N Aqueous HCl (55 mL) was added, and the organic layer was separated and washed with brine. After concentrating, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:15]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:15])[NH2:16]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCOC1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 40b from 3-methyl-4-(2-oxo-[1,3]oxazepan-3-yl)-1-nitro-benzene with palladium-charcoal under a hydrogen atmosphere in THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH3:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1cc(OC)ccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(OC)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
0.254 gram (1.4 mmole, 1.0 eq.) of product from step D was dissolved in 7 ml of 1,2-dichloroethane, after which 0.20 ml of benzoyl chloride and 0.225 gram aluminum (III) chloride (1.7 mmole, 1.2 eq. each) were added. Stirred at room temperature under nitrogen atmosphere for 75 minutes, then quenched with aqueous potassium carbonate. Diluted further with water and extracted 3× with dichloromethane. The combined organics were dried over sodium sulfate, filtered and evaporated. The resulting crude material was chromatographed to give 0.38 gram (95% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[C@H:16]1([NH2:23])[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1>CS(C)=O>[Cl:15][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)=[N:7][C:2]([NH:22][C@H:19]2[CH2:20][CH2:21][C@H:16]([NH2:23])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: Fc1cccc(-c2nc(Cl)ncc2Cl)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(F)n3)n2)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine (37 mg, 0.152 mmol), DMSO (1.5 ml) and trans-cyclohexane-1,4-diamine (87 mg, 0.758 mmol)reaction mixture was stirred at about 75° C. for about 2 hours. The reaction mixture was cooled, filter and purified by prep LC, and then lyophilized to yield 39.5 mg of the title compound as a TFA salt. LCMS (m/z): 322.2 (MH+), retention time=0.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]3[O:27][CH2:26]3)[C:20]([O:22]C)=O)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C=CC=CC=1.C(N(CC)CC)C.[SH:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:25]([CH2:26][S:49][C:50]4[S:51][CH:52]=[CH:53][N:54]=4)[O:27][C:20]3=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(OCc1ccccc1)C1CO1
Reactant: Sc1nccs1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC3C(=O)OC(CSc4nccs4)C3OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-3-phenylmethoxy-4,5-epoxypentanoate 63e (285 mg, 0.558 mmol) is dissolved in benzene/triethylamine (2.5 mL, 0.101 mmol) and 2-mercaptothiazole (164 mg, 1.40 mmol) is added. The resulting mixture is then stirred at room temperature for four hours. The mixture is diluted with ethyl acetate and water and extracted with ethyl acetate (3 times). The organic layer is washed with water and brine, then dried over magnesium sulfate and concentrated to a clear oil. The crude material is adsorbed onto silica and purified over a silica column eluting with ethyl acetate/hexane (2/8) followed with ethyl acetate/hexane (1/1). Product fractions are combined and the solvent is removed in vacuo to give the desired product as a clear oil.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][CH2:24][Mg+].[Br-]>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (5.23 g, 16.66 mmol) in anhydrous toluene (80 mL) at −20° C. was added EtMgBr (3 M in Et2O, 16.7 mL, 49.97 mmol) slowly. The reaction was allowed to warm to 0° C., and stirred at this temperature for 2 h. The reaction was quenched with 1 M HCl at 0° C. and extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3, brine, concentrated to give (S)-tert-butyl 1-cyclohexyl-3-oxopentan-2-ylcarbamate. The product was used in the next step without further purification. MS ESI +ve m/z 306 (M+Na).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]([OH:40])(=[O:39])[CH2:29][C:30]([CH2:35][C:36]([OH:38])=[O:37])([C:32]([OH:34])=[O:33])[OH:31]>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]([O-:40])(=[O:39])[CH2:29][C:30]([CH2:35][C:36]([O-:38])=[O:37])([C:32]([O-:34])=[O:33])[OH:31]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CC(C)=O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Quetiapine free base (5.0 g) was dissolved in acetone (50 ml) at room temperature. This was followed by the addition of citric acid (1.1 g) at 30 to 35° C. The resulting mass was heated at reflux and maintained for 30 minutes. This was followed by the distillation of acetone and obtained solid was further dried under vacuum to give the title compound as off white powder (3.95 g).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][C:19]([NH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:20].Cl>O1CCCC1.CCCCCC.O>[CH3:13][O:14][C:15]1[CH:34]=[C:33]([CH:35]([OH:36])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][C:19]([NH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:20]
Reactant: COc1cc(C=O)ccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: COP(C)(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(C(O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl methylphosphonate (19.5 ml) in anhydrous tetrahydrofuran (300 ml) is added a 1.72 M solution of n-butyl lithium in n-hexane (107 ml) at -50° C. Thirty minutes later, to the mixture is added in portions 2-(2-methoxy-4-formylphenoxymethylcarbonylamino)benzothiazole (20.5 g) under nitrogen atmosphere. The mixture is stirred at -50° C. for one hour, and thereto is added water. The mixture is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1→30:1) to give dimethyl {2-[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:21])[CH2:19][OH:20])[CH:12]=[CH:11]2>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:21])[CH2:19][O:20][S:1](=[O:4])(=[O:3])[NH2:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Reactant: NS(=O)(=O)Cl
Product: COc1ccc2cc(C(C)COS(N)(=O)=O)ccc2c1
Yield: 21 %

Procedure:
The title compound was prepared by the procedure of Example 28 from sulfamoyl chloride and 2-(6-methoxy-2-naphthyl)propanol as white solid, mp 112°-115° C., in 21% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([CH3:13])[CH:7]=[CH:6][C:5]1=2.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH2:16]([N:15]([CH3:14])[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([CH3:13])[CH:7]=[CH:6][C:5]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: Cn1ccc2c1CCCC2CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCC1CCCc2c1ccn2C)Cc1ccccc1
Yield: 28 %

Procedure:
A mixture of 4-(2-chloroethyl)-1-methyl-4,5,6,7-tetrahydro-1H-indole (0.1 g, 0.5 mmol), N-methyl-N-benzylamine (0.07 g, 0.5 mmol), K2CO3 (0.20 g, 1.45 mmol) and a catalytic amount of NaI in DMF (5 mL) is heated to 110° C. overnight. The solvent is removed at reduced pressure, diethyl ether is added to the residue and washed with water. The organic phase is dried and evaporated at reduced pressure and the resulting crude is purified by column chromatography, giving N-benzyl-N-methyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indol-4-yl)ethanamine (0.04 g, 0.14 mmol, 28%, oil). (ESI-MS m/z 283 (M+H)+.
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][C:9]1[N:18]=[C:17]([N:19]2[CH2:25][C:24]3[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=3[O:22][CH2:21][CH2:20]2)[C:16]2[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][CH2:12][C:11]=2[N:10]=1.[NH2:35][C:36]1[C:41]([S:42]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)(=[O:44])=[O:43])=[CH:40][C:39](Br)=[CH:38][N:37]=1>>[NH2:35][C:36]1[C:41]([S:42]([NH:45][CH2:46][CH:47]2[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]2)(=[O:44])=[O:43])=[CH:40][C:39]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]4[C:16]5[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][CH2:12][C:11]=5[N:10]=[C:9]([CH3:8])[N:18]=4)[CH2:25][C:24]=3[CH:26]=2)=[CH:38][N:37]=1
Reactant: CN1CCC(CNS(=O)(=O)c2cc(Br)cnc2N)CC1
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Agent: CC(=O)CC(=O)O
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NCC6CCN(C)CC6)c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as a diacetate salt according to the method of example 5 by using [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 2-amino-5-bromo-N-((1-methylpiperidin-4-yl)methyl)pyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, 1H), 8.05 (d, 1H), 7.60 (d, 1H), 7.45 (dd, 1H), 7.03 (d, 1H), 6.67 (br s, 2H), 4.57 (s, 2H), 4.30-4.24 (m, 2H), 3.86-3.79 (m, 2H), 2.70-2.61 (m, 6H), 2.40 (s, 2H), 2.33 (s, 3H), 2.08 (s, 3H), 1.87 (s, 6H), 1.69 (t, 2H), 1.62-1.50 (m, 4H), 1.32-1.19 (m, 1H), 1.08-0.95 (m, 2H), 0.84 (s, 6H); MS (EI) for C32H43N7O3S: 606 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:13]([CH2:25][CH2:26][OH:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:33]([N:35]=C=O)=[O:34].C(=O)([O-])O.[Na+].C(N(CC)CC)C>O1CCCC1.CO>[C:33]([O:27][CH2:26][CH2:25][C:13]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=1)(=[O:34])[NH2:35]
Reactant: CC(C)c1nc(CCO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -20 °C
Yield: 98 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 467 mg (1 mmol) of 5-(3,5-dichlorophenylthio)-2-(2-hydroxyethyl)-4-isopropyl-1-p-nitrobenzyl-1H-imidazole (126a), and there was added 0.23 g (1.2 mmol) of trichloroacetylisocyanate under stirring on a cooling bath at -20° C. Then, the bath was taken off, and the mixture was reacted for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. The extract was washed with water, dried, and the solvent was distilled off, and the trichloroacetylcarbamoyloxy compound which was able to use for the next reaction, was obtained in the residue. The intermediate was dissolved in 10 ml of aqueous methanol (10%), followed by addition of 0.2 ml of triethylamine under stirring at room temperature, and the mixture was stirred with heating at 50° C. for 3 hours and worked up. When the crystals were precipitated, the mixture was filtered directly. When the crystals were not precipitated, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with methylene chloride. The extract was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 2-(2-carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (128a) as oil (yield 98%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2C.C(N(CC)CC)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:28]([O:27][C:26]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:2])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(F)cc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cccnc2)cc2cc(F)ccc21
Reaction time: 15 h

Procedure:
To a solution of 5-fluoro-2-pyridin-3-yl-indole (Example 3, 0.100 g, 0.452 mmol) in DMF (1 mL) is added triethylamine (0.083 g, 0.814 mmol), DMAP (0.006 g, 0.045 mmol) and di-tert-butyl carbonate (0.120 g, 0.543 mmol). After 15 h, the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried over MgSO4, filtered and the filtrate is concentrated in vacuo to give a residue which is purified by silica gel chromatography (heptane-ethyl acetate, 9:1 to 4:1) to give 5-fluoro-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a yellow oil. Trituration with ether and heptane, followed by standing for several days affords a solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 9H), 6.58 (s, 1H), 7.07-7.12 (m, 1H), 7.23 (dd, J=8.6, 2.5 Hz, 1H), 7.36 (dd, J=7.8, 5.1 Hz, 1H), 7.72-7.75 (m, 1H), 8.21 (dd, J=9.1, 4.9 Hz, 1H), 8.62 (dd, J=4.9, 1.5 Hz, 1H), 8.69 (d, J=1.5 Hz, 1H). MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]([O-])(O)=O.[Na+]>CO.O1CCOCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5 g (31.6 mmol) 2-amino-6-fluorobenzoic acid are dissolved in 50 ml of methanol and combined with 7.9 ml (31.6 mmol) of a 4 M solution of HCL in 1,4-dioxane and stirred for 10 min. at ambient temperature. The reaction mixture is combined dropwise with 3.45 ml (47.4 mmol) thionyl chloride and refluxed for 3 h. Then the reaction mixture is neutralised with 150 ml of a saturated, aqueous NaHCO3 solution and extracted four times with 100 ml of ethyl acetate. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:48]1[CH2:52][CH2:51][CH2:50][C@H:49]1[CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C.ClCCl>[N:54]1([CH2:53][C@@H:49]2[CH2:50][CH2:51][CH2:52][N:48]2[C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 63.7 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 100 mL 10% DMF/dichloromethane using 4-(5-cyano-thiophen-2-yl)-benzoic acid (CAS 402765-55-9) (2.75 g, 12.0 mmol), EDC-HCl (3.44 g, 18.0 mmol), HOBt (2.43 g, 18.0 mmol), DIEA (5.22 mL, 30 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.54 g, 10.0 mmol) to give the title compound (2.33 g, 64% yield). MS (ES+) 366.2 (M+H)+
Reaction SMILES: B(C1C=CC(CCCC(O)=O)=CC=1)(O)O.[C:16]([C:18]1[CH:19]=[C:20]([NH:29][C:30](=[O:49])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([B:40]3[O:45]CC(C)(C)C[O:41]3)=[CH:36][C:35]=2[CH3:48])[CH:21]=[CH:22][C:23]=1[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])#[N:17].[OH-].[Na+]>>[C:16]([C:18]1[CH:19]=[C:20]([NH:29][C:30](=[O:49])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([B:40]([OH:41])[OH:45])=[CH:36][C:35]=2[CH3:48])[CH:21]=[CH:22][C:23]=1[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])#[N:17]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2C)cc1C#N
Agent: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2C)cc1C#N
Yield: 62 %

Procedure:
Using a procedure analogous to that used to prepare 2B, 8C (212 mg, 0.44 mmol) was reacted with NaOH and then purified by silica gel chromatography (MeOH/DCM) to afford 8D (113 mg, 62%). 1H NMR (400 MHz, THF-d8) δ 1.21 (t, 3 H), 1.94-2.04 (m, 2 H), 2.40 (t, J=7.25 Hz, 2 H), 2.70 (t, J=7.47 Hz, 2 H), 3.31 (q, J=7.47 Hz, 2 H), 7.01 (s, 2 H), 7.08 (d, J=7.47 Hz, 1 H), 7.53 (d, J=7.47 Hz, 1 H), 7.56 (s, 1 H), 7.93 (dd, 1 H), 7.99 (d, 1 H), 1.00 (d, J=2.20 Hz, 1 H), 9.66 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH:10]3[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27](Cl)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]>>[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH:10]5[C:9]4=[O:17])=[CH:6][N:7]=3)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]
Reactant: Nc1ccc(N2CCN3CCCC3C2=O)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 64.7 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.050 g, 0.215 mmol) was combined with 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.066 g, 0.215 mmol, 1.0 eq), and gave 7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a beige solid (75 mg, 0.139 mmol), in 65% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.52 (m, 4H) 1.72-1.90 (m, 2H) 1.90-2.00 (m, 6H) 2.00-2.18 (m, 2H) 2.21-2.39 (m, 1H) 2.52-2.82 (m, 3H) 2.95-3.14 (m, 3H) 3.15-3.27 (m, 8H) 3.42 (t, J=8.28 Hz, 1H) 3.66 (dt, J=11.54, 4.02 Hz, 1H) 3.95 (ddd, J=11.80, 9.29, 4.52 Hz, 1H) 4.27-4.41 (m, 1H) 6.45 (s, 1H) 7.69 (dd, J=9.03, 2.51 Hz, 1H) 8.11 (s, 1H) 8.25 (d, J=2.51 Hz, 1H) 8.65 (d, J=9.03 Hz, 1H) 8.73 (s, 1H); HRMS calc for m/z=503.2883 and found m/z=503.2892 (M+H).