Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1C=C[C:6](CN)=[CH:5][CH:4]=1)#[N:2].Br[C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[N:25]([CH:27]=[CH:28][N:29]=3)[CH:26]=2)=[O:18])=[CH:15][N:16]=1.BrC1SC(C(NC2C=CC3N(C=CN=3)C=2)=[O:37])=CN=1>>[N:29]1[CH:28]=[CH:27][N:25]2[CH:26]=[C:21]([CH2:20][NH:19][C:17]([C:14]3[S:13][C:12]([NH:2][CH2:1][CH:3]4[CH2:4][CH2:5][CH2:6][O:37]4)=[N:16][CH:15]=3)=[O:18])[CH:22]=[CH:23][C:24]=12
Reactant: O=C(Nc1ccc2nccn2c1)c1cnc(Br)s1
Reactant: O=C(NCc1ccc2nccn2c1)c1cnc(Br)s1
Reactant: N#Cc1ccc(CN)cc1
Product: O=C(NCc1ccc2nccn2c1)c1cnc(NCC2CCCO2)s1

Procedure:
The title compound was prepared as in Example 53B, substituting (tetrahydrofuran-2-yl)methanamine for 4-cyanobenzylamine and 2-bromo-N-(imidazo[1,2-a]pyridin-6-ylmethyl)thiazole-5-carboxamide for 2-bromo-N-(imidazo[1,2-a]pyridin-6-yl)thiazole-5-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([CH3:19])[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][O:28][CH3:29].[CH:30](N(CC)C(C)C)([CH3:32])[CH3:31]>O1CCCC1>[CH3:27][O:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]([CH2:31][CH2:30][CH3:32])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([CH3:19])[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Cc1c(C)nc(-c2ccccc2)nc1-c1cccc(O)c1
Reactant: COCBr
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1cccc(OCOC)c1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
Methyl 2-(4-(3-hydroxyphenyl)-6-methyl-2-phenylpyrimidin-5-yl)acetate (150 mg; 0.449 mmol), bromo(methoxy)methane (73.3 μL; 0.897 mmol) and N,N-Diisopropylethylamine (116 μL; 0.673 mmol) were added to a flask at room temperature, dissolved in tetrahydrofuran (449 μL) and heated to reflux for 1 h. The reaction mixture was cooled to room temperature. The salts were removed by filtration and the filtrate was washed with water, brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to give 86 mg (49%) of the title compound as a colorless oil. ESI/APCI(+): 378 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](NCCCNC(=O)CN1CCN(C2C=CN=CC=2)CC1)(=[O:13])=[O:12].NCCCN.C(Cl)[Cl:40]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([Cl:40])(=[O:13])=[O:12]
Reactant: O=C(CN1CCN(c2ccncc2)CC1)NCCCNS(=O)(=O)c1ccc2ccccc2c1
Reactant: ClCCl
Agent: NCCCN
Product: O=S(=O)(Cl)c1ccc2ccccc2c1

Procedure:
The N-(3-aminopropyl)naphthalene-2-sulphonamide used as a starting material was obtained by the reaction of 2-naphthylsulphonyl chloride (2 g) and 1,3-diaminopropane (2.95 ml) in methylene chloride (25 ml) solution at ambient temperature for 16 hours.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[C:46]([CH2:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:48])[NH2:47]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:53]2[CH2:54][CH2:55][CH2:56][N:50]([CH2:49][C:46](=[O:48])[NH2:47])[CH2:51][CH2:52]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: NC(=O)CN1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Yield: 82.3 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 5.69 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 2.48 g of N,N'-carbonyldiimidazole and 5.89 g of N-carbamoylmethylhomopiperazine bis(trifluoroacetate), 4.88 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1scc2c1OCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=496.3.
Reaction SMILES: [C:1]([C:3]#[C:4][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O)([CH3:7])[CH3:6])#[N:2].[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:13][C:12]2[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]#[C:3][C:1]#[N:2])[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(C(C)(C)C#CC#N)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C#CC#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 64 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][C:7]([CH3:9])=[N:6][NH:5][C:4]1=[O:10].[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO.O>[CH3:9][C:7]1[CH2:8][N:3]([N:2]=[CH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:10])[NH:5][N:6]=1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=NNC(=O)N(N=Cc2cccnc2)C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 164 g of 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride in 500 ml methanol a 50% NaOH solution is added until a pH of 6 is reached. Now 486 g of a solution containing 22% 3-pyridinaldehyde in water is added maintaining a temperature below 70° C. After the addition is completed the reaction mixture is kept at 65° C. for two hours. Then the suspension is cooled to about 5° C., filtered and dried to yield the title compound.
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])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C(Cl)Cl.N1C(C)=CC=CC=1C.[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][S:29]([C:28]([F:34])([F:33])[F:27])(=[O:31])=[O:30]
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a dry 1 L RBF containing 6,7-dimethoxy-quinolin-4-ol (20.9 g, 102 mmol), which can be prepared according to the procedure of Riegel, B. (J. Amer. Chem. Soc. 1946, 68, 1264), was added DCM (500 mL), 4-dimethylaminopyridine (1.24 g, 10 mmol) and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirred at RT. Trifluoromethanesulfonyl chloride (14 mL, 132 mmol) was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). 1H NMR (400 MHz, DMSO, d6): δ 8.82 (d, 1H), 7.59 (m, 2H), 7.20 (s, 1H), 3.97 (d, 6H). LC/MS: M+H=338.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([N:15]1[CH2:47][CH2:46][CH2:45][C@H:16]1[C:17]([NH:19][C@H:20]([C:42]([NH2:44])=[O:43])[CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)=O.C(OCC)(=O)C>O>[NH2:1][C@H:2]([C:13]([N:15]1[CH2:47][CH2:46][CH2:45][C@H:16]1[C:17]([NH:19][C@H:20]([C:42]([NH2:44])=[O:43])[CH2:21][S:22][C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
To the Boc-Trp-Pro-Cys(Trt)-NH2 (100 gm), added formic acid (800 ml) at temperature of about 20° C. to about 35° C. Stirred for 60 minutes at same temperature and charged ethyl acetate, DM water to the reaction mass and separated the aqueous and organic layers. Washed the organic layer with DM water and separated the layers. Taken organic layer and cooled to about 0° C. to about 10° C. and adjusted pH to 10-12 with 8N aqueous sodium hydroxide solution. Heated the solution to about 25° C. to about 35° C. and separated the organic layer. Concentrated the organic layer under reduced pressure to obtain the residue, which was crystallized from isopropyl ether to obtain H-Trp-Pro-Cys(Trt)-NH2 as white solid material.
Reaction SMILES: CN(C=O)C.[CH:6]1[C:23]2[C:22]3[CH:21]=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]4)=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C(=O)N([Br:31])C(=O)C1.BrC1CC(=O)NC1=O>O>[Br:31][C:14]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:23]=3[C:22]=2[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: c1ccc2cc3c(ccc4ccccc43)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CC(Br)C(=O)N1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2cc2c1ccc1ccccc12
Yield: 91.6 %

Procedure:
Into 300 ml of DMF, N,N-dimethylformamide, 40 g of commercial benzanthracene was dispersed, and 35.6 g of NBS, bromosuccinimide, was added to the resultant suspension at the room temperature. After the resultant mixture was stirred for 3.5 hours, 600 ml of water was added, and the formed crystals were separated by filtration and washed with methanol. The obtained crude crystals were purified using a silica gel column with toluene and filtered with hexane, and 49.3 g of 7-bromobenzanthracene was obtained as cream crystals (the yield: 91%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([CH2:25][CH3:26])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:27][N:28]([CH:30]=[O:31])[CH3:29].N1C[CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34]C1>C1COCC1>[CH2:25]([C:19]1[CH:18]=[C:17]([CH2:16][CH:11]([NH:10][C:30]([N:28]2[CH2:29][CH2:34][CH:35]([N:38]3[CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:48])[CH2:36][CH2:27]2)=[O:31])[C:12]([O:14][CH3:15])=[O:13])[CH:22]=[CH:21][C:20]=1[CH2:23][CH3:24])[CH3:26]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCc1ccc(CC(N)C(=O)OC)cc1CC
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
3.3 mL ethyldiisopropyl-amine and 2.06 g (12.6 mmol) of CDT were added to an ice-cooled solution of 2.95 g (12.54 mmol) of methyl 2-amino-3-(3,4-diethyl-phenyl)-propionate in 200 mL of THF and stirred for a further 90 min at 0-10° C. Then 20 mL of DMF were added, the mixture was stirred for a further 30 min, 2.91 g (12.6 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were added and the suspension was refluxed for 10 h. The reaction mixture was evaporated down in vacuo, combined with semisaturated NaHCO3 solution, exhaustively extracted with EtOAc and dried over MgSO4. After elimination of the desiccant and solvent the crude product was reacted without any further purification.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH3:31])[CH:21]=1.[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:39]=1)([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:40]3[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=3)[C:37]([NH:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:51])[CH2:50][CH2:49]2)=[O:26])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (6.31 g, 9.92 mmol, 5.91 ml) was added dropwise to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1 g, 5 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.5150 g, 5,5 mol) and triethylamine (1.508 g, 14.88 mmol, 2.068 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.71 g). MS (ESI) m/z 459.7 [M+H]+
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2].[CH2:32]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:32])[CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Solvent: O=CO
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1C

Procedure:
A 400 mg portion of 1-ethyl-6-fluoro-7-[3[(hexyloxy)methyl]-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added to a mixture of 1.2 ml of 37% formaldehyde and 1.5 ml of 90% formic acid. The mixture was heated on a steam bath for one hour, evaporated to an oil, diluted with 5 ml of water and neutralized with 1N sodium hydroxide. The solid was collected and dried, giving 360 mg of the desired product, mp 172°-174° C.
Reaction SMILES: C(=[N:14][NH:15][C:16]1[C:17]2[CH:54]=[CH:53][CH:52]=[CH:51][C:18]=2[S:19][C:20]=1[C:21]([C:23]1[N:27](COCC2C=CC=CC=2)[C:26]2[CH:37]=[C:38]([O:41][CH2:42][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:39]=[CH:40][C:25]=2[N:24]=1)=O)(C1C=CC=CC=1)C1C=CC=CC=1.Br>C(O)C>[N:45]1([CH2:44][CH2:43][CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:25]3[N:24]=[C:23]([C:21]4[C:20]5[S:19][C:18]6[CH:51]=[CH:52][CH:53]=[CH:54][C:17]=6[C:16]=5[NH:15][N:14]=4)[NH:27][C:26]=3[CH:37]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(c1sc2ccccc2c1NN=C(c1ccccc1)c1ccccc1)c1nc2ccc(OCCCN3CCCCC3)cc2n1COCc1ccccc1
Agent: Br
Solvent: CCO
Product: c1ccc2c(c1)sc1c(-c3nc4ccc(OCCCN5CCCCC5)cc4[nH]3)n[nH]c12
Temperature: 90 °C
Yield: 61.3 %

Procedure:
A mixture of [3-(N′-benzhydrylidene-hydrazino)-benzo[b]thiophen-2-yl]-[1-benzyloxymethyl-6-(3-piperidin-1-yl-propoxy)-1H-benzoimidazol-2-yl]-methanone [200 mg, Intermediate (43)] and concentrated HBr (2 ml) in ethanol (4 ml) was heated at 90° C. overnight. The solution cooled to room temperature and the mixture was passed through a SCX column. Eluting with 7N ammonia in methanol yields 3-[6-(3-piperidin-1-yl-propoxy)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole (72.1 mg). This material was dissolved in HCl/1,4-dioxane (2 ml, 4M) and methanol (0.05 ml) and the mixture was concentrated and dried to afford 3-[6-(3-piperidin-1-yl-propoxy)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole hydrochloride [85.1 mg, Example 55]. LC/MS: 432 (M+H), RT=2.49 minutes; 1H NMR [(CD3)2SO]: δ9.6 (1H, s), 8.0 (1H, t), 7.4 (2H, m), 7.3 (1H, s), 7.2 (1H, m), 6.9 (1H, m), 6.8 (1H, m), 4.2 (2H, t), 3.6-3.7 (4H, m), 3.5-3.6 (2H, m), 3.4 (1H, m), 3.2 (1H, m), 2.8 (2H, m), 2.2 (2H, m), 1.8 (1H, m), 1.4 (1H, m).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)[Cl:9])=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:24]([NH2:32])(=[NH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC.O1CCCC1>[ClH:9].[NH2:32][C:24](=[N:31][C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[N:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1COCCN1
Reactant: N=C(N)c1ccccc1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: NC(=NC(=Nc1ccccc1)N1CCOCC1)c1ccccc1
Reaction time: 22 h
Yield: 32.8 %

Procedure:
To 3.48 g (0.02 mol) of phenylisocyanide dichloride in 25 ml of anhydrous ether at 0° C. under a nitrogen atmosphere was added 1.74 g (0.02 mol) of morpholine and 2.02 g (0.02 mol) of triethylamine in 20 ml of ether dropwise. The mixture was stirred for 22 hours and filtered to remove the precipitated triethylamine hydrochloride. To a solution of 4.8 g (0.04 mol) of benzamidine in 15 ml of anhydrous tetrahydrofuran at 0° C. was added the above filtrate dropwise. The mixture was stirred for 22 hours at ambient temperature. The precipitated crude product was collected, washed with anhydrous ether, chromatographed on 150 g of silica gel using 1:6 methanol-dichloromethane and recrystallized from methanol-ether to afford 2.26 g (32%) of N-(1-amino-1-phenylmethylene)-N'-phenyl-4-morpholinecarboximidamide hydrochloride, mp 247°-248° C.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21](O)=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N3CCCCC3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
A mixture of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (400 mg, 1.12 mmol), piperidine (143 mg, 1.68 mmol), HATU (512 g, 1.34 mmol) and DIPEA (230 mg, 1.79 mmol) in DMF (4 mL) was allowed to stir at RT overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (8×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc gave an oily residue which was purified by reverse phase HPLC followed by chiral HPLC to afford 10 mg of (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone, and its enantiomer. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.30 (d, 6H), 1.40-1.90 (m, 6H), 1.92-2.12 (m, 5H), 2.30-2.42 (m, 1H), 2.65-2.81 (m, 4H), 2.90-3.01 (m, 1H), 3.40-3.90 (m, 6H), 5.00-5.08 (m, 1H), 6.00 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)(C)C.C(OCC)C>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NC2CCN(Cc3ccccc3)C2)c2ncnn12
Temperature: 85 °C

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.1 g, 0.36 mmol), (R)-1-Benzyl -pyrrolidin-3-ylamine (0.07 g, 0.396 mmol, 1.10 equiv.) and DiPEA (0.15 mL, 0.72 mmol, 2.00 equiv.) are mixed in isopropanol (5 mL) under nitrogen. The reaction is heated to 85° C. until completion of the reaction (typically 5 h). The mixture is then allowed to cool down to room temperature and diluted with diethyl ether, causing the precipitation of the title compound as a solid that is used without further treatment.
Reaction SMILES: N1C=CC(C(Cl)=O)=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38]([N:40]=[C:41]=[S:42])=[O:39])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][C:35]([C:38]([N:40]=[C:41]=[S:42])=[O:39])=[CH:34][CH:33]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:35]2[CH:34]=[CH:33][N:32]=[CH:37][CH:36]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccncc1
Agent: O=C(N=C=S)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccncc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Pyridinecarbonyl isothiocyanate was prepared using commercially available 4-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 94%).