Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1.CCOC(C)=O>O>[CH3:2][NH:3][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To melted methylamine hydrochloride (Aldrich, 73.7 g, 1090 mmol) at 235° C. (oil bath) was added 6-(2-chloropyridin-4-yloxy)-1-naphthoic acid (6.54 g, 21.8 mmol). The reaction mixture was stirred for 3 min and cooled to RT. The brownish solid was treated with EtOAc and water and stirred until all residue was either in solution or suspended. The precipitate was filtered off, washed with EtOAC and purified by silica gel chromatography using 0-100% of a 85:15:0.5 mixture of DCM:MeOH:AcOH. The product obtained was washed with water, filtered and dried under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c(N)cccc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cccc12
Yield: 93.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-amino-quinoline-4-carboxylic acid methyl ester (Intermediate 475) (370 mg, 1.38 mmol), 2-nitrobenzenesulfonyl chloride (530 mg, 2.3 mmol), DMAP (cat.), pyridine (0.44 ml, 5.4 mmol) and DCM (15 ml) gave the title compound (500 mg, 70%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([S:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:44][CH:43]=1)(=[O:47])=[O:46])[O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A mixture of (3R,3aS, 6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(l-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-benzyloxybenzenesulphonyl chloride (134 mg, 0.474 mmol), diisoproylethylamine (0.083 mL, 0.474 mmol) and dimethylaminopyridine (1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction mixture was warmed to 55° C. and an additional quantity of dimethylaminopyridine (˜2 mg) was added. After stirring for 2 hours, the reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). After separating the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (235 mg, 74%) as a foam. H1-NMR (chloroform-D3): 0.94 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.74 (m, 2H), 3.98 (m, 4H), 4.18 (m, 1H), 4.88 (d, 1H), 5.08 (m, 1H), 5.19 (s, 2H), 5.70 (d, 1H), 7.13 (d, 2H), 7.34 (m, 10H), 7.80 (d, 2H). MS(ESI): 691(M+Na).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:25]([C@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1ccccc1)C(=O)O
Yield: 45 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylalanine to provide the title compound in 45% yield as yellow needles (recrystallization from MeOH/water).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:14])[CH:12]=[CH2:13]>>[NH:1]1[C:2]2=[N:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]2[CH2:13][CH2:12][C:11]1=[O:14]
Reactant: C=CC(=O)OCC
Reactant: Nc1nc2ccccc2[nH]1
Product: O=C1CCn2c(nc3ccccc32)N1
Temperature: 130 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
5.32 g (40 mmol) 2-aminobenzimidazole and 4.00 (40 mmol) ethyl acrylate were dissolved in 25 ml Proglyde DMM. The reaction mixture was heated to 130° C. and the reaction was allowed to continue for 6 hours at 130° C. The reaction mixture was allowed to cool down to room temperature. Upon standing over night, 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one crystallized from the medium and was isolated by filtration. 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one was recrystallized from 1-methoxy-2-propanol. 4.1 g (54.7%) 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated (m.p. >260° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].Cl[CH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:24]1[C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]=[CH:35][C:23]=1[CH2:22][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: ClCc1ccc2oc3ccccc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (75 mg, 303 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.15 mL, 0.30 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (70 mg, 323 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave, after evaporation and drying, 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (11 mg, 8% yield). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.20 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol hydrochloride 7 as a pale brown solid (11 mg, 8% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[N:20]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[N:17]=1>CN(C)C=O>[CH2:24]([O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[N:17]=[C:16]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH3:25]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CCOC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1c(OC2CCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 34.64 parts of ethyl 4-hydroxy-1-piperidinecarboxylate and 940 parts of N,N-dimethylformamide were added portionwise 10 parts of a sodium hydride dispersion 50% at room temperature under nitrogen atmosphere. Upon complete addition, stirring was continued for 1 hour at room temperature. A solution of 45 parts of 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole in N,N-dimethylformamide was added dropwise at 50° C. Upon completion, the whole was stirred overnight at 50° C. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 50 parts (69.1%) of ethyl 4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate as a residue (compound 19).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.ClC(Cl)C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].Cl>O.ClCCl>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:24][C:19]=1[CH3:18]
Reactant: COc1ccccc1C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of succinic anhydride (12.0 g, 122.0 mmol) and 50 mL of 1,1,2,2,-tetrachloroethane at room temperature was added AlCl3 (21.5 g, 161.2 mmol) and 2-methylanisole (Compound 1, 10 mL, 81.0 mmol). The resulting solution was stirred for 4 h at room temperature, then poured into a solution of concentrated HCl (20 mL) in water (50 mL) and ice. Dichloromethane was added, and the bottom layer was separated. The solvents were removed under reduced pressure, and the residue was dissolved in a boiling solution of sodium carbonate (30 g Na2CO3 in 160 mL H2O) for 10 min, and filtered. The filtrate was acidified with concentrated HCl to pH=0-1, and crystallized in a salt ice bath. The solid product was filtered and washed with cold water, and dried in the air to give 13.7 g (76%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(OC(C)C)(=O)C.[F:13][C:14]1([F:65])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C@@H:28](O)[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=3[N:23]=[C:22]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:41][N:40]=4)[CH2:35][CH2:34]3)[C:21]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:16][CH2:15]1>>[CH3:1][S:2]([O:5][C@H:28]1[CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][C:24]2[N:23]=[C:22]([CH:33]3[CH2:34][CH2:35][N:36]([C:39]4[N:40]=[CH:41][C:42]([O:45][CH2:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:43][N:44]=4)[CH2:37][CH2:38]3)[C:21]([C@@H:53]([F:64])[C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:61])[F:63])=[CH:58][CH:59]=3)=[C:20]([CH:17]3[CH2:18][CH2:19][C:14]([F:65])([F:13])[CH2:15][CH2:16]3)[C:29]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Solvent: CC(=O)OC(C)C
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](OS(C)(=O)=O)C1
Yield: 80.2 %

Procedure:
Reactions similar to those of Example 13 were performed except for using 3.8 μl (57 μmol) of methanesulfonic acid instead of 35% hydrochloric acid and using 1.5 ml of isopropyl acetate instead of acetone, and from 40.0 mg (52.0 μmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 28, 35.3 mg of the title compound was obtained as a white powder (yield: 78%).
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[S:5][C:6]2[C:11]([NH:12][C@H:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][OH:15])=[N:10][C:9]([S:20][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH3:22])=[N:8][C:7]=2[N:30]=1.[CH3:31]O>[Na+].[Cl-]>[F:29][C:25]1[CH:24]=[C:23]([C@@H:21]([S:20][C:9]2[N:10]=[C:11]([NH:12][C@H:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][OH:15])[C:6]3[S:5][C:4]([O:1][CH3:31])=[N:30][C:7]=3[N:8]=2)[CH3:22])[CH:28]=[CH:27][CH:26]=1
Reactant: CO
Reactant: [OH-]
Reactant: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cccc(F)c2)nc2nc(Cl)sc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: COc1nc2nc(S[C@@H](C)c3cccc(F)c3)nc(N[C@@H](CO)CC(C)C)c2s1
Temperature: 50 °C

Procedure:
KOH (0.063 g, 1.12 mmol) was added to (2R)-2-[(2-chloro-5-{[(1S)-1-(3-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol in MeOH (5 mL) and the mixture was heated to 50° C. After 4 h the mixture was diluted with NaCl (aq) and extracted with CHCl3, the organic phase was dried (MgSO4) and evaporated to give the title compound.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([OH:31])(=[O:30])[C@H:27]([CH3:29])[OH:28]>C1COCC1.ClCCl>[O:28]([C@@H:27]([CH3:29])[C:26]([OH:31])=[O:30])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
A solution of t-butylchlorodiphenylsilane, TBDPSCl, (7.9 g, 28.9 mmoL) in THF (20 mL) was slowly added via canula into a solution of triethylamine (7.4 mL, 53.1 mmol), DMAP(catalytic amount) and L-(+)-lactic acid 9 (2.0954 g, 26.16 mmol) in THF (20 mL) and dichloromethane (20 mL) at room temperature. The resulting mixture, a white suspension, was stirred at room temperature for 2 days. The reaction mixture was washed sequentially with water, 3N HCl and water, dried over Na2SO4, filtered and solvent was removed under vacuum. The product was purified by column chromatography on silica using EtOAc/hexane=1/3 and 1/1 as eluent to obtain 4.965 g (58%) of 10.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.O>C1COCC1>[C:11]([C:9]1[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(CO)nn1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
To a solution of compound 3h (0.8 g, 2.28 mmol) in 25 mL of THF was added LiAlH4 (0.14 g, 3.65 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAc (50 mL) and water (50 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes=7/3) to give the titled compound (0.56 g, 80% yield) as a white solid. mp 143.0-146.5° C. 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 6.26 (s, 1H), 5.10 (t, J=6 Hz, 1H), 4.39 (d, J=6 Hz, 2H), 3.32 (s, 3H), 1.14 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Product: Cc1cccc2c1C(=CNc1ccc(OCC3CCCN(C)C3)cc1)C(=O)N2
Yield: 51 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (603 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.28 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (439 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](=[N:19]/[H])/[NH:17][OH:18])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[S:31]1[CH:35]=[CH:34][C:33]([C:36](OCC)=O)=[CH:32]1>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[N:19]=[C:36]([C:33]4[CH:34]=[CH:35][S:31][CH:32]=4)[O:18][N:17]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccsc1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3ccsc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 150 °C

Procedure:
A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1 ml) was treated with a 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) and ethyl 3-thiophenecarboxylate (18 μl, 0.13 mmol). The mixture was heated in the microwave at 150° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous extracted again with EtOAc. The combined extracts were concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[C:28]([CH2:30][C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH2:6][CH2:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32])#[N:29]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (86 mg, 87%), MS (ISP) m/z=398.3 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyano-acetic acid.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 32 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and acetyl chloride as starting material, 17.5 mg (32%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 7.95 (2H), 7.92 (s, 1H), 7.48 (d, 1H), 7.43-7.36 (m, 5H), 6.56 (s, 1H), 5.60 (s, 2H), 4.75-4.69 (m, 1H), 4.47 (s, 2H), 3.98-3.92 (m, 1H), 3.54-3.46 (m, 1H), 3.31-3.28 (m, 1H), 2.80-2.72 (m, 1H), 2.24-2.20 (m, 2H), 2.10 (s, 3H), 1.75-1.64 (m, 2H); LC-MS m/z [M+H]+ 483.2, RT 3.02 min.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: c1nc[nH]n1
Reactant: COc1cc(Br)ccc1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-n2cncn2)ccc1N
Temperature: 110 °C
Yield: 47 %

Procedure:
A mixture of 4-bromo-2-methoxyaniline (208 mg, 1.03 mmol), 1,2,4-triazole (80 mg, 1.13 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (20 mg, 0.103 mmol) in DMF was heated at 110° C. for 20 h. Further portions of 1,2,4-triazole (0.1 g, 1.44 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (0.1 g, 0.52 mmol) were added and the mixture was heated a further 72 h at 110° C. The mixture was cooled, diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The combined aqueous washes were re-extracted with ethyl acetate (20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline as a light red solid (92 mg, 47%). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H); 8.05 (s, 1H); 7.11 (d, J=2.3, 1H); 6.99 (dd, J=8.3, 2.3, 1H); 6.74 (d, J=8.3, 1H); 3.97 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[N:7]=[C:8]([S:12][CH3:13])[N:9]=[CH:10][C:11]=2[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: CSc1ncc2c(C)c[nH]c(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc2c(C)cnc(Cl)c2n1
Yield: 52 %

Procedure:
A solution of 5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 186, 48 mg, 0.232 mmol) in POCl3 (1.5 mL) was heated to 70° C. for 2 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried and adsorbed on silica. The residue was purified by silica gel column chromatography eluting with 0 to 15% EtOAc in cyclohexanes to give the title compound (27 mg, 52%).