Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[C:18]=2[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: N#Cc1cccc2c1CCNC2
Product: N#Cc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:31][C:32]([NH2:34])=[S:33]>C(O)C>[NH2:34][C:32]1[S:33][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:31]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(=O)CBr
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(2,6-dichlorobenzyloxyimino)-3-oxobutyrate (7.2 g) was dissolved in ethanol (20 ml) and N,N-dimethylaniline (2.33 ml) and thiourea (1.4 g) added with stirring. After 18 h the title compound was filtered off, washed with ethanol and dried (4.9 g), m.p. 171°-2° C., νmax (KBr) 3423, 1722, 1619, 1529, 1284, 1188, 1021, and 995 cm-1, δH [(CD3)2SO]1.22 (3H, t), 4.33 (2H, q), 5.51 (2H, s), 6.96 (1H, s), 7.24 (2H, br s), and 7.54 (3H, m), [Mass spectrum: M+ (373/375)].
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=O)[CH2:28]Cl)[CH3:23]>CCO>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27]1[N:21]=[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13](=[O:14])[NH:12][CH2:11][C:1]34[CH2:2][CH:3]5[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]5)[CH2:10]3)[CH2:8]4)[N:16]2[CH:28]=1)[CH3:23]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Solvent: CCO
Product: CCOC(=O)Cc1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Temperature: 25 °C

Procedure:
A mixture of N-(1-adamantylmethyl)-6-aminopyridine-2-carboxamide (1.4 g, 4.9 mmol) and 4-chloro-3-oxo-butyric acid ethyl ester (808 mg, 4.9 mmol) in EtOH (20 mL) is heated under reflux for 20 h. After cooling to RT, the solvent is removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous sodium carbonate. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The brown residue is purified by re-crystallization from 2% MeOH in CH2Cl2 to give the title compound. 1H-NMR (δ, ppm, CDCl3 as internal standard): 8.39 (s, 1H), 7.71 (d, 1H), 7.16 (t, 1H), 7.06 (d, 1H), 6.22 (m, 1H), 4.20 (q, 2H), 3.87 (s, 2H), 3.20 (d, 2H), 2.02 (m, 3H), 1.78-1.58 (m, 12H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(N)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1ccc(C#N)cc1)[Si](C)(C)C
Yield: 95.2 %

Procedure:
About 5.09 g of 4-aminobenzonitrile, 10.03 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 22.02 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 40 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)amino]benzonitrile (4-BTMSABZN) as a brown oil (10.77 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 6.93 (doublet, 2H, aromatic protons), 6.43 (doublet, 2H, aromatic protons), −0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@H:4]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:19][C:20]([F:41])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:41][C:20]([F:19])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27](/[CH:30]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:26][CH2:25]1
Reactant: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of N,N-dimethyl-3-(methylsulfonyl)-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-alaninamide (150 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (173 mg) in 2-propanol (5 mL) was added piperidinium acetate (74 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (55 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][C:13]3=[O:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH:13]3[OH:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccc(N3CCCC3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CCCc2ccc(N3CCCC3)cc21

Procedure:
To a solution of 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-one (0.548 g, 2.55 mmol) in methanol (20 mL) at 0° C. is added sodium borohydride (0.241 g, 3.54 mmol) and the reaction is stirred for 1.5 hours, whereupon water is added and the volatiles are removed in vacuo. The mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated to give 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CN(C)[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Yield: 45.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]amide (45 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (95 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.4.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C@H:23]1[CH2:26][C@H:25]([C:27](O)=[O:28])[CH2:24]1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:27]([C@H:25]2[CH2:26][C@H:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])[CH2:24]2)=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C1)N1Cc2ccncc2C1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(N[C@H]1C[C@H](C(=O)NCCCc2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-phenylpropylamine for 3-phenylpropan-1-amine and trans-3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)cyclobutanecarboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.75 (t, J=5.5 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.32-7.24 (m, 2H), 7.24-7.13 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 4.66-4.55 (m, 4H), 4.41-4.27 (m, 1H), 3.11-3.03 (m, 2H), 2.89-2.75 (m, 1H), 2.62-2.52 (m, 2H), 2.39-2.25 (m, 2H), 2.26-2.11 (m, 2H), 1.76-1.63 (m, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([OH:26])[C:24]#[CH:25]>[Cu]I.C(NCC)C>[C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][OH:26])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C#CCO)ncc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A mixture of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii)) (0.96 g), propargyl alcohol (0.16 g), copper (I) iodide, bis-triphenylphosphine palladium is dichloride (0.035 g) and diethylamine (10 ml) was stirred together at room temperature for 20 hours. The mixture was concentrated and the residue partitioned between ethyl acetate and 1M aqueous hydrochloric acid solution (2×25 ml) and the mixture was extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:iso-hexane (1:4 to 1:1) and then ethyl acetate to afford the sub-titled compound (0.48 g) as an oil.
Reaction SMILES: C(Cl)(=O)C.C(OC(=O)[NH:11][C@H:12]1[C@H:21]([O:22][CH3:23])[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:24](=[O:26])[NH2:25])=[CH:17][CH:18]=2)[C:13]1([CH2:29][CH3:30])[CH2:27][CH3:28])(C)(C)C>C(O)C>[NH2:11][C@@H:12]1[C:13]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:14]2[CH:15]=[C:16]([C:24]([NH2:25])=[O:26])[CH:17]=[CH:18][C:19]=2[CH2:20][C@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
Acetyl chloride (278.8 mL, 3920 mmol) was added dropwise to ethanol (382 mL, 6530 mmol) at −5° C. over 2 h keeping the internal temperature below 20° C. The resulting solution was added portion wise over 15 min, keeping the internal temperature below 30° C., to a slurry of trans-(7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (123.0 g, 327 mmol) and ethanol (500 mL) that had been cooled to 10° C. The reaction mixture was stirred at room temperature for 2 h, and concentrated to ˜200 mL by rotary evaporation. Ethyl acetate (200 mL) was added and the resulting slurry was stirred at 0° C. for 30 min, filtered and dried to yield the hydrochloride salt of the title compound (102 g, >98% purity) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.F[B-](F)(F)F.[CH3:21][O+](C)C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([O:12][CH3:21])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: C[O+](C)C
Reactant: O=C1Nc2ccc(Cl)cc2C2CCCC12
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=Nc2ccc(Cl)cc2C2CCCC12

Procedure:
A solution of 8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (200 mg, 0.9 mmol) in dichloromethane (20 ml) is stirred with trimethyloxonium tetrafluoroborate (134 mg, 0.9 mmol) for 24 hours at room temperature. After triethylamine (0.13 ml, 0.9 mmol) is added, the batch is concentrated by evaporation and purified by column chromatography (SiO2, 40% moist) with ethyl acetate-hexane: 180 mg (85%) of product.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=CC(C#N)=C[N:11]2[N:10]=[CH:9][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOC(C)=O>[NH2:6][C:7]1[C:5]2=[CH:1][C:2]([CH:3]=[O:4])=[CH:12][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: N#Cc1cc2c(N)ncnn2c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of THF (200 mL) was added 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 6.28 mmol). The solution was heated until all stalling material was in solution and was then cooled in an ice-water bath. 1M Diisobutylaluminum hydride in THF (50.3 mL, 50.3 mmol) was then added to the solution which was stirred for 1 h. EtOAc was added to the solution and it was then allowed to warm to it. Wet silica gel was carefully pipetted into the solution, and the reaction mixture was heated to 50° C. for 30 min, filtered through Celite, and washed with excess EtOAc. The solution was transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness yielding 0.92 g of yellow solid (5.69 mmol, yield 91%). 1H-NMR (DMSO-d6) 9.91 (s, 1H) 7.92 (d, J=1.7 Hz, 1H), 8.14 (d, J=35.3 Hz, 2H), 7.89 (s, 1H), 7.30 (d, J=1.8 Hz, 1H); MS [M+H]+=163.3; LCMS RT=1.07 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Br:13][C:14]1[C:15](Cl)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Br:13][C:14]1[C:15]([NH:1][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)c1cccc(F)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Br
Yield: 28.5 %

Procedure:
A solution of 2-amino-3-fluoro-N-methyl-benzamide (625 mg, 3.72 mmol), 5-bromo-2,4-dichloro-pyrimidine (1025 mg, 4.498 mmol), and N,N-diisopropylethylamine (1250 uL, 7.18 mmol) in N-methylpyrrolidinone (10.0 mL) was heated at 100° C. overnight. Solvent was removed by rotary evaporation and the residue was triturated with DCM to afford 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a yellow solid (381 mg, 28%) that had the following properties: 1H-NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 7.51-7.44 (m, 3H), 2.73 (d, J=4.4, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[N:24][C:15]2=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[N:24][C:15]2=3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3cccnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COc2cccnc2N1C1CCNCC1
Reaction time: 2.5 h
Yield: 93.5 %

Procedure:
To a stirring solution of 0.37 g (0.0011 mol) of 4-(3-oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2.5 mL) was added 2.5 mL of TFA. After 2.5 h, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4, and concentrated to afford 0.24 g (94%) of a white/pink solid. 1H NMR (400 MHz, CDCl3): 7.87 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=7.8 Hz, 1.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 4.8 Hz, 1H), 4.98-4.83 (m, 1H), 4.45 (s, 2H), 3.90 (s, 1H), 3.06 (d, J=8.3 Hz, 2H), 2.65-2.53 (m, 4H), 1.65-1.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A solution of 9.3 g (0.032 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in approximately 30 ml of N,N-dimethylformamide was added to a stirred mixture of 1.5 g (0.030 mole) of sodium hydride (50% suspension in oil) in 100 ml of N,N-dimethylformamide. The mixture was stirred for 15 minutes and 4.50 g (0.0304 mole) of 4-fluoronitrobenzene was added. This mixture was stirred at room temperature for approximately 18 hours then was heated at 80° C. for five hours. The mixture was cooled, poured into ice water and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a solid residue. This residue was purified by recrystallization from n-heptane to yield 8.1 g of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, m.p. 109°-110° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)=O.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[N:4]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(N)=S
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
17 mg (1.5 mmol) of thiourea is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 9 mg (17%) of 8-(2-amino-thiazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13]([OH:15])=[O:14])=[O:4].[N:24]12[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]1)[C@@H:26](O)[CH2:25]2.O.N1(O)C2C=CC=CC=2N=N1.C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[CH3:23][O:22][C:19]1[N:18]=[CH:17][C:16]([CH:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:13](=[O:15])[O:14][C@@H:26]2[CH:27]3[CH2:30][CH2:31][N:24]([CH2:29][CH2:28]3)[CH2:25]2)=[CH:21][CH:20]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccccc1NC(C(=O)O)c1ccc(OC)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-(methoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I79) (118 mg, 0.37 mmol), (R)-quinuclidin-3-ol (52.2 mg, 0.41 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (62.8 mg, 0.41 mmol), and N,N′-methanediylidenedicyclohexanamine (85 mg, 0.41 mmol) was dissolved in dry THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: O=C1NCCN1C1C=C(C=CN=1)C([O-])=O.[O:16]=[C:17]1[NH:21][N:20]=[CH:19][N:18]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:21]2[C:17](=[O:16])[N:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[N:20]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Agent: O=C([O-])c1ccnc(N2CCNC2=O)c1
Product: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Yield: 65 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 2-(2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate to react with 1-(bromomethyl)-4-fluorobenzene, methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate was obtained as a colorless solid in 65% yield: MS (ES+) m/z 328.9 (M+1).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[F:32][CH:3]([F:2])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:30][CH2:31]1)=[O:25]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2-propanesulfonyl chloride. Light-yellow solid. MS (m/z): 541.3 (M+H)+.