Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@@H:12]([CH3:13])[CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][C:20]3[C@H:26]([CH3:27])[C@H:25]4[N:22]([C:23](=[O:35])[C@@H:24]4[C@H:28]([O:30][Si](C)(C)C)[CH3:29])[C:21]=3[C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[S:17][CH:18]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[C@@H:12]([CH3:13])[CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][C:20]3[C@H:26]([CH3:27])[C@H:25]4[N:22]([C:23](=[O:35])[C@@H:24]4[C@H:28]([OH:30])[CH3:29])[C:21]=3[C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[S:17][CH:18]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (640 mg, 1.04 mmol) in THF (30 ml) was added at 0° C. water and then the solution was adjusted to pH about 3 with 1N hydrochloric acid and stirred for 10 minutes. To the reaction solution was added an aqueous sodium hydrogen carbonate solution and the reaction mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1/2) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (547 mg, 97%) as a pale yellowish amorphous.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O>[N:32]1([CH2:2][CH2:3][C:4]2[CH:19]=[CH:18][C:7]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=3)=[CH:6][CH:5]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: NC(=O)c1ccc(Oc2ccc(CCO)cc2)nc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN3CCCCC3)cc2)nc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
Dissolve 6-[4-(2-hydroxy-ethyl)-phenoxy]-nicotinamide (100 mg, 0.38 mmol) under N2 atmosphere in dry DMF (4 mL). Add Et3N (108 μL, 0.77 mmol) then cool the mixture at 0° C., add MsCl (29 μL, 0.38 mmol), allow the mixture to warm to room temperature. After 1 hour add piperidine (76 μL, 0.77 mmol) and heat the mixture at 90° C. for 1 hour. Cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over MgSO4. Eliminate the solvent. Purify by flash chromatography on silica gel (eluent: CHCl3/5% EtOH/0.5% NH4OH) to give the title compound (65 mg, 55%). Electrospray MS M+1 ion=326, 1H-NMR (CDCl3, 400 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4 end 8.5 Hz), 7.25-7.23 (m, 2H), 7.07-7.03 (m, 2H), 6.93 (d, 1H, J=8.5 Hz), 6.12 (bs, 2H), 2.88-2.80 (m, 2H), 2.68-2.65 (m, 2H), 2.53-2.44 (m, 4H), 1.67-1.59 (m, 4H), 1.51-1.43 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37]>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CC(C)(C)OC(=O)CN
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC(=O)OC(C)(C)C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 48.9 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.193 g of glycine tert-butyl ester instead of the N-Boc-ethylenediamine used in example 52c. 0.174 g of tert-butyl {[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}-acetate is obtained with the following characteristics:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:15]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[C:16]1([N:15]([CH:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CN2CCCCC2CN(c2ccccc2)C2Cc3ccccc3C2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(N(CC2CCCCN2)C2Cc3ccccc3C2)cc1

Procedure:
A solution of compound 15 (1.5 g, 3.79 mmol) in methanol (50 mL) was purged with argon for 20 minutes. Ammonium formate (2.33 g, 37.87 mmol) was then added and the solution was purged for another 10 minutes. Pd—C (10%; 216 mg) was added and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was filtered through the Celite® reagent and washed with methanol. The filtrate was concentrated and the crude material was purified by chromatography on 230-400 mesh silica gel eluting with 2% methanol-DCM to provide compound 16.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:49][C:50]1[CH:55]=[CH:54][C:53](Cl)=[C:52](Cl)[CH:51]=1)[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCNc1ccc(Cl)c(Cl)c1
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccccc1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 122G, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 50 mg, 0.079 mmol) and N-butyl-3,4-dichloroaniline (Aldrich, 10 mg, 0.046 mmol) were converted to the title compound. 1H NMR (1:1 CD3OD:CDCl3, mixture of amide rotamers) δ 8.73 (s, 1H), 8.12-8.00 (m, 4H), 7.97-7.94 (m, 1H), 7.74-7.66 (m, 2H), 7.57 (br s, 1H), 7.46 (br s, 1H), 7.36 (br s, 1H), 7.26-7.19 (m, 4.5H), 7.12-7.10 (m, 0.5H), 7.00 (br s, 1H), 6.73 (br s, 1H), 6.66 (br s, 0.5H), 6.50 (br s, 0.5H), 4.66 (br s, 0.5H), 4.51 (br s, 0.5H), 4.39 (br s, 0.5H), 4.25 (br s, 0.5H), 3.85 (br s, 2H), 3.58 (br s, 2H), 3.13 (br s, 1H), 2.81 (br s, 1H), 2.20-2.16 (m, 3H), 1.38-1.21 (m, 4H), 0.93-0.83 (m, 3H); MS(ESI+) m/z 760.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.[CH:65]1([C:68](Cl)=[O:69])[CH2:67][CH2:66]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:68]([CH:65]3[CH2:67][CH2:66]3)=[O:69])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.FC1[N:44]=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:1][C:2]1[N:44]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (6-fluoropyridin-3-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=516, obsd.=516).
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)=[O:8])=[CH:31][N:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Reactant: Nc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 50 mg, 0.124 mmol), (2-aminopyrimidin-5-yl)boronic acid (26 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) was flushed with argon and PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added. The mixture was subjected to MW irradiation 140° C. for 30 min, passed through a PL-Thiol MP SPE cartridge (StratoSpheres™), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 5) tR=1.53 min, m/z=461.1 [M+H]+, m/z=459.1 [M−H]−.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(=O)O)nc(N)n1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(N)n1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (110 mg, clear pale yellow oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (150 mg, 0.56 mmol, Amine-17, single enantiomer) and 2-amino-6-methylpyrimidine-4-carboxylic acid (85 mg, 0.56 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:18]([O-:20])=[O:19])=[C:5]2[OH:12]
Reactant: Oc1ccnc2ccc(Cl)nc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1O
Temperature: 100 °C
Yield: 90 %

Procedure:
6-chloro-1,5-naphthyridin-4-ol (1.45 g, 8 mmol) was added to ice-cooled conc. H2SO4 (15 mL) and followed by the addition of KNO3 (1.62 g, 16 mmol) slowly at 0° C. The mixture was heated to 100° C. for 1 h, and then was poured into ice-water. The precipitate was collected and dried in vacuo to afford 6-chloro-3-nitro-1,5-naphthyridin-4-ol as a solid in 90% yield (1.97 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(O)C.[Pd]>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][N:3]=[C:4]([NH2:10])[N:5]=1
Reactant: COc1cc(Cl)nc(N)n1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccnc(N)n1
Reaction time: 14 h
Yield: 89.4 %

Procedure:
To a solution of 4-chloro-6-methoxypyrimidine-2-ylamine (4.4 g, 27.7 mmol) in EtOAc (200 mL) and ethanol (150 mL), was added diisopropylethylamine (9.6 mL, 55.3 mmol) and 10% palladium on carbon (2.9 g, 2.77 mmol). The heterogeneous solution was stirred under a balloon atmosphere of H2 for 14 hours, at which time the solution was filtered through a Celite pad and the volatiles were removed in vacuo. The residue was dissolved in EtOAc (200 mL), washed with Na2CO3(sat) (100 mL) and with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 3.1 g (90%) of 4-methoxypyrimidine-2-ylamine. LCMS (m/z): 126 (MH+). 1H NMR (CDCl3): δ 8.00 (d, J=5.7 Hz, 1H), 6.08 (d, J=5.7 Hz, 1H), 4.98 (bs, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C(C)=NC=CC=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ncccc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cccnc2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a orange solid, MS (ISP): m/e=323.1 (M+H+).
Reaction SMILES: N1C[CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]C1.[CH3:17][N:18]([CH3:21])[CH:19]=O.[C:22](=[O:25])([O-])[O-].[K+].[K+]>O>[O:25]([CH2:22][CH2:17][N:18]1[CH2:21][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCN(CCOc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8 g of 3-[1,2,3,6-tetrahydro-4-pyridinyl]-5-chloro-1H-indole [described in French Pat. No. 2,362,628], 80 ml of dimethylformamide, 7.5 g of potassium carbonate and 9 g of β-bromo-phenethanol was stirred at 50° C. under an inert atmosphere for 2 hours and was then cooled to room temperature and was slowly diluted with 400 ml of distilled water. The mixture was stirred for 30 minutes and was vacuum filtered. The recovered product was washed with water, then with a 1-1 water-ethanol mixture and dried to obtain 14 g of raw product. 15.8 g of the said product were chromatographed over silica gel and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture. The product was crystallized from ethanol to obtain 11.53 g of 3-[1-(2-phenoxyethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-5-chloro-1H-indole melting at 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([CH:23]=O)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([CH2:23][NH:29][CH3:28])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2cccc(Cl)c2)c1-c1ccccc1
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2cccc(Cl)c2)c(-c2ccccc2)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution (15 mL) of methyl 1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (700 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (4.3 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (20 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (76 mg), N-methylmorpholine N-oxide (377 mg) and molecular sieves 4A powder (1.5 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give 1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde as a brown solid (yield 565 mg, 88%). 1-[(3-Chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (560 mg) was dissolved in methanol (25 mL), and methylammonium chloride (1.05 g) and sodium cyanoborohydride (294 mg) were added. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→ethyl acetate). The obtained oil was dissolved in ethyl acetate (5 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. The precipitated crystals were collected by filtration and vacuum-dried to give the title compound as a colorless solid (yield 154 mg, 24%).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=O.[OH-].[Na+]>C(O)CC>[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:17]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CN(C)C=CC(=O)c1ccccn1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1ccc(-c2ccnc(Nc3cccc(-n4ccnc4)c3)n2)nc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Thirteen and seven tenths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 8.8 g of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one (3), 50 ml of n-propanol and 10 ml of 10N sodium hydroxide is refluxed for 18 hours. The reaction is diluted with 50 ml of n-propanol and filtered. The collected yellow solid is stirred in 300 ml of water for 0.5 hour, filtered and washed with 50 ml of n-propanol followed by 100 ml of diethyl ether. The solid is air dried overnight giving 13.4 g (85%) of the desired product, mp 210°-211° C. The overall yield following this procedure is 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Li+]>O1CCCC1>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N
Product: O=C(O)CCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.6 %

Procedure:
To a solution of methyl 4-{(3R)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}butanoate (80 mg) in tetrahydrofuran (5 mL) was added 1M aqueous lithium hydroxide (1 mL). The mixture was stirred overnight at room temperature. The mixture was then loaded directly onto an SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated at reduced pressure and the residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then SCX-2 column eluting with methanol then 7M NH3 in methanol to give the title compound as a white solid (60 mg, 77%).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]([C:5]1[NH:6][C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4].Cl.N[C:16]1NC=C(CCCC(NCCCCCCCCCCCC)=O)N=1>>[Cl:13][C:2]([Cl:1])([Cl:12])[C:3]([C:5]1[N:6]([CH3:16])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: O=C(c1cc(Br)c(Br)[nH]1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCNC(=O)CCCc1c[nH]c(N)n1
Agent: Cl
Product: Cn1c(C(=O)C(Cl)(Cl)Cl)cc(Br)c1Br
Yield: 96 %

Procedure:
Using the same general procedure as used for the synthesis of 2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)-ethanone 8, 5.00 g of 2-trichloroacetyl-1-methyl pyrrole 12 gave 8.14 g (96%) of the title compound 14 as white needles. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.86, 123.81, 122.68, 120.58, 99.58, 94.89, 37.60; HRMS (FAB) calcd for C7H4Br2Cl3NO (M+) 380.7725. found 380.7744.