Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:39][N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH:40][CH3:39])=[O:28])=[CH:30][CH:31]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC)cc3)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a mixture of 0.053 g (0.12 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-138), 0.06 g (0.15 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.03 mL (0.186 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes, a solution of 0.09 mL (0.186 mmole) of 2M methylamine in tetrahydrofuran was added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70) to give 0.036 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-methyl-benzamide (I-140).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](=[O:13])[CH:7](Br)[C:6]=2[CH:15]=1.CS(C)=[O:19]>>[Br:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](=[O:13])[C:7](=[O:19])[C:6]=2[CH:15]=1
Reactant: O=C1C2CC(C2)c2cc(F)c(Br)cc2C1Br
Reactant: CS(C)=O
Product: O=C1C(=O)C2CC(C2)c2cc(F)c(Br)cc21
Yield: 72 %

Procedure:
A solution of 2,9-dibromo-3-fluoro-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (1.04 g at 65% purity LC-UV215) in dimethylsulfoxide (15 mL) was warmed to 80° C. for 1 hr. Evaporation of the reaction mixture (high vacuum distillation) furnished the crude title compound (0.87 g at 72% purity LC-UV215) as a golden-brown syrup which was carried through to the next synthetic step without purification. 1H NMR (500 MHz, CDCl3) δ 2.25-2.30 (m, 2H), 3.12-3.18 (m, 2H), 3.48-3.51 (m, 1H), 3.61-3.65 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H); M+1=305/307.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7])([CH3:3])[CH3:2].[Br:13][C:14]1[N:18]2[N:19]=[C:20](Cl)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1.CCN(C(C)C)C(C)C>>[CH:1]([O:4][C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][NH:11][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([Br:13])=[CH:15][N:16]=2)[N:19]=1)[CH3:7])([CH3:3])[CH3:2]
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CC(C)OC(=O)N(C)CCCN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N(C)CCCNc1ccc2ncc(Br)n2n1
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A stirred mixture of (3-amino-propyl)-methyl-carbamic acid isopropyl ester (3.0 g, 17.0 mmol), 3-bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (723.7 mg, 3.1 mmol), and Hunig's base [7087-68-5] (0.6 mL, 3.2 mmol) was heated to 85° C., under N2 blanket, for 3d then preabsorbed on silica gel and flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) to obtain 1.0 g of clear yellow oil. LRMS (ESI) m/z 370.2/372.2 [(M+H)]+, calc'd for C14H20BrN5O2: 370.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:7]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH3:44])=[C:41]([O:45][CH3:46])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:36]([C:35]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([O:43][CH3:44])[C:34]=2[Cl:33])=[O:37])[CH:7]=1
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Reactant: CC(C)CCNCc1nc2ccccn2c1Cc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccn3c2Cc2cc(Br)ccc2O)c(Cl)c1OC
Temperature: 45 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 90 mg (0.25 mmol) ({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(3-methylbutyl)amine in 4 mL dichloromethane at 0° C. is treated with triethylamine 50 mg (0.50 mmol) and then 2-chloro-3,4-dimethoxybenzoylchloride 110 mg (0.50 mmol). The solution is stirred overnight and the volatiles removed by rotary evaporation. The residue is dissolved in 4 mL methanol and treated with 2 mL 1M sodium hydroxide. The solution is heated to 45° C. for 1 hr and the volatiles removed by rotary evaporation. The mixture is acidified with 1M hydrochloric acid, extracted with 3×5 mL ethyl acetate and the combined extracts washed with 5 mL brine. The combined extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to yield 120 mg (80%) N-({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 602.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH2:19]([C:26]1([OH:32])[CH2:31][CH2:30][N:29]([CH2:16][CH:14]([OH:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])=[CH:8][CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC2CO2)cc1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 89.1 %

Procedure:
(RS)-tert-Butyl-dimethyl-(4-oxiranylmethyl-phenoxy)-silane (0.62 g, 2.34 mmol) was dissolved in MeOH (8 ml) and stirred overnight at room temperature in the presence of 4-benzyl-4-hydroxy-piperidine (0.9 g, 4.68 mmol). The reaction mixture was concentrated and the residue was chromatographed over silica gel (hexane-ethylacetate 1:1, then CH2Cl2 --MeOH 19:1) to provide (RS)-4-Benzyl-1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-hydroxy-propyl}-piperidin-4-ol (0.95 g, 90%) as a yellow oil, MS: m/e=456.5 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[C:28]2[C:33](=[N:34][CH:35]=1)[N:32]([C@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:37]1)[CH:31]=[C:30]([C:50]([O:52]CC)=[O:51])[C:29]2=[O:55].C([O-])([O-])=O.[Cs+].[Cs+].[Li+].[OH-]>O1CCOCC1.O.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>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:26]2[CH:27]=[C:28]3[C:33](=[N:34][CH:35]=2)[N:32]([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)[CH2:37]2)[CH:31]=[C:30]([C:50]([OH:52])=[O:51])[C:29]3=[O:55])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cn([C@H]2CCCN(CCN3CCOCC3)C2)c2ncc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3C2CCCN(CCN3CCOCC3)C2)cn1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 0.350 g, 0.97 mmol) and (S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 34, 0.480 g, 0.97 mmol) were taken up in dioxane (4 mL), Cs2CO3 (0.633 g, 1.94 mmol) in water (1.000 mL) was added followed by Pd(PPh3)4 (0.112 g, 0.10 mmol). The reaction mixture was heated to 100° C. for 2 h, then 2 ml of 2N LiOH were added and stirred at 100° C. for an additional 30 min. The reaction mixture was cooled to room temperature and solvent evaporated. The resulting residue was taken back up in DMSO (2 ml) and filtered. DMSO solution was purified on an ISCO C18 column using water and acetonitrile. (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (0.080 g, 12%) is recovered as a pale yellow solid.
Reaction SMILES: CC[C@@H]([C@H](NC([C@@H](NC(CNC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@H]1NC(=O)[C@H]([C@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@@H](NC([C@@H](N)CCCCN)=O)CSSC1)=O)C)=O)[C@H](O)C)=O)CCC(N)=O)=O)CCCNC(N)=N)=O)CC(C)C)=O)C)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)CC(C)C)=O)C(C)C)=O)CC1NC=NC=1)=O)CO)=O)CO)=O)CC(N)=O)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)=O)C)=O)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H:76]([C:85]([OH:87])=[O:86])[CH2:77]C1C=CC(O)=CC=1)=O)[C@H](O)C)=O)CC(N)=O)=O)CO)=O)=O)C(C)C)=O)CC(N)=O)=O)[C@H](O)C)=O)CO)=O)CO)=O)CC(C)C)=O)C.[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277]>>[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277].[C:85]([O-:87])(=[O:86])[CH:76]([CH3:77])[OH:274]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)[C@@H](C)O)C(C)C)[C@@H](C)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)[O-]

Procedure:
At t=-30, vehicle, or amylin±AC-0253 was begun. Amylin dose rates were 50, 100 and 300 pmol/kg/min. Dose rates of AC-0253 were 500 and 1500 pmol/kg/min. 25% glucose (1 gm/kg) was administered by mouth at t=0 minutes. Amylin±AC-0253 was discontinued at t=120 minutes. Samples for insulin, glucose and lactate were obtained at 15 minute intervals from t=-45 to t=180 minutes. Samples for rat amylin and AC-0253 were taken at t=60 and 120 minutes.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[K+].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[S:17]>>[CH3:14][N:15]([C:16]([O:9][C:4]1[C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=[CH:6][CH:5]=1)=[S:17])[CH3:19]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1ccccc1C(F)(F)F
Yield: 89 %

Procedure:
If the procedure described in Preparation XI is followed starting from 3.95 g (24.3.10-3 mol) of 2-trifluoromethylphenol, 1.43 g (25.6.10-3 mol) of potassium hydroxide and 3.46 g (28.10-3 mol) of dimethylthiocarbamoyl chloride, 5.37 g (yield: 89%) of a yellow oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:36][C:37]([F:49])([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:37]([F:36])([F:48])[F:49])=[CH:44][CH:43]=3)=[C:11]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:23])=[CH:34][CH:35]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2O)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A DCM solution (1 mL) containing the intermediate from Step A (22 mg, 0.043 mmol), copper(II) acetate (8 mg, 0.043 mmol), 4-(trifluoromethoxy)phenyl boronic acid (18 mg, 0.086 mmol), triethylamine (0.03 mL, 0.215 mmol) and 4 Å molecular sieves (small spatula tip) was stirred under an air atmosphere. After stirring overnight the solution was filtered and concentrated to give tert-butyl N-[4-(2-{3′,4′-dichloro-4-[4-(trifluoromethoxy)phenoxy]biphenyl-3-yl}ethyl)benzoyl]-β-alaninate. LCMS1 4.85 min. (M+H)=674. The tert butyl group was cleaved as described in EXAMPLE 1 Step I to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J=8.2 Hz, 2H); 7.59 (d, J=2.2 Hz, 1H); 7.51 (d, J=8.3 Hz, 1H); 7.37-7.34 (m, 3H); 7.24 (d, J=8.3 Hz, 2H); 7.21 (d, J=8.4 Hz, 2H); 6.98-6.95 (m, 4H); 3.79 (q, J=5.9 Hz, 2H); 3.01 (s, 4H); 2.80 (t, J=5.8 Hz, 2H). LCMS1 4.43 min. (M+H)=618.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]([CH3:31])[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]1)[N:11]=[CH:10][N:9]=2)=[O:5].[CH3:33][Mg]Cl>C1COCC1>[C:4]([C:6]1[N:7]([CH3:31])[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]1)[N:11]=[CH:10][N:9]=2)(=[O:5])[CH3:33]
Reactant: CON(C)C(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
N-Methoxy-N,9-dimethyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide (30 mg, 0.07 mmol) was dissolved into THF (2 mL) under nitrogen and cooled to −78° C. Methylmagnesium chloride (3 M in THF; 0.046 mL, 0.14 mmol) was added to the reaction mixture. The reaction was stirred at −78° C. for 30 minutes and slowly warmed to room temperature. After 1 hour, the crude reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated potassium carbonate. The organic layer was collected, was concentrated, was dissolved into methanol and was purified by preparative HPLC to afford 1-[1-(8-acetyl-9-methyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (9.3 mg, 0.023 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.35 (s, 1H), 7.20-7.14 (m, 1H), 6.96-6.88 (m, 3H), 6.27-4.92 (m, 2H), 4.66-4.45 (m, 1H), 3.93 (s, 3H), 3.42-3.20 (m, 2H), 2.63 (s, 3H), 2.42-2.26 (m, 2H), 1.87 (br d, 2H). MS (EI) for C20H21N7O2: 392 (MH+).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH:16]([NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:17])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([NH:47][CH:48]2[CH2:53][C:52]([CH3:55])([CH3:54])[NH:51][C:50]([CH3:57])([CH3:56])[CH2:49]2)[N:42]=1>>[NH2:18][CH:16]([CH3:17])[CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:45]3[CH:46]=[CH:41][N:42]=[C:43]([NH:47][CH:48]4[CH2:53][C:52]([CH3:55])([CH3:54])[NH:51][C:50]([CH3:57])([CH3:56])[CH2:49]4)[N:44]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC(Cc1ccc2ccn([Si](C)(C)C(C)(C)C)c2c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC(N)Cc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1

Procedure:
The title compound was prepared as described in Example 215, starting from {2-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-6-yl]-1-methyl-ethyl}-trityl-amine (prepared by trityl and TBDMS protection of 2-(1H-Indol-6-yl)-1-methyl-ethylamine) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ removal of the protecting groups with 2N-HCl. Yield: 406 mg (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3Cl)=[O:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(C(=O)c4cccc(Cl)c4)cnc23)CC1
Temperature: 150 °C
Yield: 38.6 %

Procedure:
A stirred suspension of (3-chlorophenyl)(8-chloro-3-quinolinyl)methanone (D5)(0.63 g, 2.1 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (0.43 g, 2.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.058 g, 0.064 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.074 g, 0.19 mmol) and sodium tert-butoxide (0.22 g, 2.3 mmol) in degassed toluene (3.5 ml) was heated in a sealed tube at 150° C. for 10 mins in a microwave oven. The cooled reaction mixture was washed with water (20 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compound (D6) as a yellow foam (0.37 g, 0.81 mmol, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:29][C@H:28]([CH3:30])[N:27]([CH3:31])[C@H:26]([CH3:32])[CH2:25]3)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:25][C@H:26]([CH3:32])[N:27]([CH3:31])[C@H:28]([CH3:30])[CH2:29]3)[CH:22]=2)[CH:17]=[CH:16]1)=[O:14]
Reactant: C[C@@H]1CN(c2ccc3c(c2)N(C(=O)Cc2cccc(C(F)(F)F)c2Cl)CC3)C[C@H](C)N1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3ccn(C(=O)Cc4cccc(C(F)(F)F)c4Cl)c3c2)C[C@H](C)N1C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
A solution of E8 (1.8 g, 3.86 mmole) in DCM (150 ml) was treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (908 mg, 4.0 mmole) in DCM (50 ml) and the mixture stirred at room temp. under argon for 20 mins. The mixture was washed with 10% Na2CO3 solution, dried (Na2SO4), and evaporated to a brown oil. Column chromatography on silica gel (eluent 5% MeOH/DCM) afforded the title compound as a yellow semi-solid (1.1 g, 61%), which was converted to its hydrochloride salt as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:31][CH2:30][CH2:29][NH:28][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCNC(C)C)cc3)cc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (intermediate 64) (66 mg, 0.180 mmol), N-isopropylethylenediamine (55.2 mg, 0.540 mmol) and cesium carbonate (58.6 mg, 0.180 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 43 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (white powder) in a yield of 53%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].O>S1(=O)(=O)CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: COc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COc1ccnc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A mixture of 2-chloro-4-methoxypyrimidine (29 g) and 1-(5-nitro-2-pyridinyl)piperazine (35 g) in tetrahydrothiophene 1,1-dioxide (50 ml) was stirred at 130° C. for 1 hour. The mixture was poured into sodium carbonate and water, stirred for 30 minutes and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. The residue was triturated in diisopropyl ether, yielding 23 g (43%) of 4-methoxy-2-[4-(5-nitro-2-pyridinyl)-1-piperazinyl]pyrimidine (interm. 10).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]([CH3:35])([CH3:34])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Yield: 99.8 %

Procedure:
A solution of Compound 312 (0.48 g) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for thirty minutes. The solvents were removed by evaporation under reduced pressure and the residue was extracted between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was saturated with sodium chloride and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give Compound 314 (0.38 g).