Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=O)=[N:14]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37]>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=[S:37])=[N:14]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1cc(C#N)cc1-c1c2c(=O)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1cc(C#N)cc1-c1c2c(=S)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 140 °C

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3yl]-1methyl-1H-pyrrole-3-carbonitrile (0.53 g) in pyridine (5 mL) was added P4S10 (0.52 g). The mixture was heated by microwave at 140° C. for 100 minutes. The mixture was diluted with water and ethyl acetate. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using a FlashMaster™ yielding 0.44 g.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:9])(=[O:3])[CH3:2]
Reactant: NCCN1CCCCC1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCC(CC(C)C)C(=O)NCCN1CCCCC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of (±)-2-[(acetylthio)methyl]-4-methylpentanoic acid in 40 ml of THF is cooled to 5° C., followed by the dropwise addition of triethylamine (1.0 g) in 5 ml of THF. This solution is cooled to -5° C. and ethyl chloroformate in 4 ml of THF is added dropwise at -5° to 0° C. It is stirred for 30 minutes and N-(2-aminoethyl)piperidine in 30 ml of THF is added dropwise. The reaction mixture is stirred at 20° C. for 4 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue is dissolved in ether and washed with aqueous NaHCO3. Ether is dried with MgSO4, filtered and concentrated in vacuo to yield 2.1 g of crude product. This crude is absorbed on a 20-g pad of alumina act II and washed through with ether to yield 1.4 g of product which crystallizes from pentane, melting point 47°-50° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][C@H:45]([CH3:53])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([NH:44][C@@H:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH3:53])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Prepared using General Procedure 7. To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (1000 mg, 1.762 mmol) and (R)-tert-butyl 2-aminopropanoate HCl (352 mg, 1.938 mmol) in DMF (8 mL). The solution was cooled to 0° C. and TEA (737 μl, 5.28 mmol) was added. To this mixture was slowly added HATU (804 mg, 2.114 mmol) over 5 mins then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with EA (150 mL) and washed with 1M HCl (100 mL) then brine (100 mL). The organic layer was isolated and dried over MgSO4. The solvents were removed to give a white solid and ACN (50 mL) was added and the suspension was sonicated. The fine suspension was stirred for 30 mins then filtered and washed with iso-hexanes to afford 881 mg (70.5%) of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-23 as a white powder. LCMS-ESI (m/z) calculated for C41H50N4O6: 694.4; no m/z observed, tR=3.39 min (Method 11). The chiral purity was calculated at >99% e.e. (Chiral Method).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,3-dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH3:16])[N:21]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43]C(C)(C)C)=O)[CH2:37][CH2:36]1>C(OCC)(=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][CH:35]5[CH2:36][CH2:37][N:38]([C:41](=[O:43])[CH2:1][N:6]([CH3:12])[CH3:7])[CH2:39][CH2:40]5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h

Procedure:
Using the general procedure for amide bond synthesis, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid was first reacted with tert-butyl 4-aminopiperidine-1-carboxylate. The product was diluted to ethyl acetate, washed by sodium bicarbonate aqueous solution and brine. Organic extract was dried and concentrated to a residue. It was then dissolved in a mixture of TFA and MeOH (1:1) and stirred for 1 h. After which, it was concentrated in vacuo, separated between ethyl acetate and sodium bicarbonate aqueous solution. Organic extract dried and concentrated to a residue, which was subjected to amide bond synthesis with 2-(dimethylamino)acetic acid. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (m, 2 H) 1.61 (m, 4 H) 1.73 (br. s., 4 H) 1.99 (s, 3 H) 2.19 (s, 6 H) 2.73 (m, 1 H) 3.14 (m, 3 H) 3.80-3.95 (m, 3 H) 3.95-4.20 (m, 4 H) 4.26 (m., 1 H) 4.81 (d, J=8.1 Hz, 1 H) 7.19 (d, J=6.8 Hz, 1 H) 7.92-8.10 (m, 2 H) 8.18-8.35 (m, 2 H). [M+H] calc'd for C30H39F3N8O4, 633; found 633.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[OH-].[Li+].Cl>CN(C)C=O.CCOCC>[CH2:16]([S:23][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
Ethyl 4-chloro-3-nitrobenzoate (10 g) and benzyl mercaptan (5.41 g) were dissolved in N,N-dimethylformamide and whilst stirring, lithium hydroxide monohydrate (1.83 g) was added. The mixture was stirred overnight then poured into ether and 2N hydrochloric acid. The organic phase was washed with water, dried over anhydrous magnesium sulphate and evaporated to yield ethyl 4-benzylthio-3-nitrobenzoate (10.16 g), obtained as an oil, NMR (CDCl3) δ1.41 (3H, t), 4.24 (2H,s), 4.40 (2H,q), 7.3-7.47 (5H), 7.53 (1H,d), 8.14 (1H,dd), 8.86 (1H,d).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=1[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].IC>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][C:13]=1[O:24][CH3:25]
Reactant: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COc1cc(S(=O)(=O)N(C)C)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A suspension of 4-(1,3-dioxoisoindolin-2-yl)-3-hydroxy-N,N-dimethylbenzenesulfonamide (Preparation 106, 83 mg, 0.240 mmol), K2CO3 (50 mg, 0.359 mmol) and iodomethane (0.1 mL, 1.60 mmol) in EtOH (4 mL) was stirred at 100° C. under microwave irradiation for 60 minutes. When cooled, the resulting crystals (50 mg, 58%) obtained were filtered, washed with EtOH and dried to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C:12]([CH3:17])([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24]>C1C=CC=CC=1>[ClH:25].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C:12]([CH3:17])([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CN(CCCc2ccccc2)CCN1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: CC1(C)CN(CCCc2ccccc2)CCN1C(=O)c1ccco1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-(3-phenylpropyl)-3,3-dimethylpiperazine [b.p. 111°C (2 mmHg), dipicrate, m.p. 195° - 200°C], 2-furoyl chloride and benzene.
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[CH3:27][NH:28][CH3:29]>C(O)C.CN(C=O)C.O>[CH3:27][N:28]([CH3:29])[CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CNC
Reactant: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(O)CN(C)C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Using an analogous reaction procedure to that described in Example 33, a mixture of 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine, 33% dimethylamine in ethanol and DMF was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The product so obtained was washed with water and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-(3-dimethylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 55% yield, m.p. 120°-122° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-nitrophenyl)ethan-1-one (1 eq) and phenylmethylamine (1 eq) in methanol was added sodium triacetoxyborohydride (1.2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative purification yielded [(4-nitrophenyl)ethyl]benzylamine. MS: MH+=256.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[CH:13][N:12]([C:15]3[S:16][C:17]([C:27]([NH2:29])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=4)[N:19]=3)[C:11]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:39]1[CH2:44][CH2:43]O[CH2:41][CH2:40]1.[CH3:45][N:46](C)C=O>>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:19]=[C:15]([N:12]3[C:11]4[CH:30]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]5[CH2:44][CH2:43][N:46]([CH3:45])[CH2:41][CH2:40]5)[CH:8]=[CH:9][C:10]=4[N:14]=[CH:13]3)[S:16][C:17]=2[C:27]([NH2:29])=[O:28])[CH:25]=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CN1CCN(CCCCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Reaction time: 3 h

Procedure:
A mixture of 0.023 g (0.05 mmole) of 2-[6-(4-chloro-butoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.37a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.013 mL (0.15 mmole) of morpholine was stirred at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.019 g of 4-(3-chloro-phenyl)-2-{6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.38) as a white powder. MH+/Z=512
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([O:20][CH3:21])=[O:19].ClC(Cl)(Cl)C(O)=O>CCOCC>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:13]1[N:12]([CH3:11])[C:16]([C:1]([C:9]#[N:10])([OH:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: COC(=O)Cc1cccn1C
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(O)(C#N)c2ccccc2)n1C

Procedure:
A solution of 6.7 g (0.05 mole) of benzoylcyanide, 7.6 g (0.05 mole) of methyl 1-methylpyrrole-2-acetate and 0.2 g of trichloroacetic acid in 20 ml. of ether was stirred for four days at 25° C. under argon. The solution was cooled to 0° and the solid methyl 5-(cyanohydroxyphenylmethyl)-1-methylpyrrole-2-acetate was collected by filtration; mp 148°-153°, yield, 4.0 g (28 percent).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12.[C:14](Cl)(Cl)=[O:15].[CH3:18][OH:19]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]1([C:18]([O:15][CH3:14])=[O:19])[C:2]2[CH:3]=[C:4]3[CH2:13][CH2:12][CH2:11][CH2:10][N:5]3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)cc1n2CCCC1
Reactant: CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1cc1n2CCCC1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
6,7,8,9-tetrahydropyrido[1,2-a]indole (1.15 g, 6.7 mmol) in methylene chloride (5 ml) was added dropwise at 0° C. to a solution of phosgene (10 mmol) in toluene (5 ml). The reaction mixture was stirred for one hour after which methanol (1 ml) was added gradually and the mixture allowed to warm to ambient temperature. The solvent was removed under reduced pressure to yield a white solid. Recrystallization from hexane afforded 1.08 g (70.3% of methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-1-carboxylate, as white crystals, m.p. 102°-103° C. Anal. for C14H15NO2 : Calcd. C, 73.34; H, 6.59; N, 6.11. Found: C, 72.96; H, 6.61; N, 6.33.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(N)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:23][C:22]1[CH:21]=[C:20]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[CH2:7][CH2:6]2)[CH:26]=[CH:25][CH:24]=1
Reactant: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Nc1cccc(I)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1cccc(C#CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c1
Yield: 68.5 %

Procedure:
A solution of 1-(3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine (263 mg, 1.00 mmol), 3-iodoaniline (208 mg, 0.950 mmol) and tetrakis(triphenylphosphine) palladium (0) (46 mg) in n-butylamine (5 mL) is allowed to reflux for 15 hr. The solvent is evaporated in vacuo to give a residue, which is purified by flash chromatography giving the product as an off white solid (231 mg, 69%): mp 139-140° C.; 1H NMR (CDCl3) 1.71 (m, 3 H), 2.12 (m, 2 H), 2.56 (m, 4 H), 2.73 (m, 2 H), 2.84 (m, 2 H), 3.60 (bs, 2 H), 6.59 (d, J=7.5 Hz, 1 H), 6.72 (s, 1 H), 6.79 (d, J=7.5 Hz, 1 H), 7.07 (dd, J1=J2=7.5 Hz, 1 H), 7.33 (d, J=9.7 Hz, 2 H), 7.46 (d, J=9.7 Hz, 2 H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=2)[CH2:3][CH2:2]1.CO[Na].CO.[CH2:29](I)[CH3:30]>CS(C)=O.O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH3:30])=[CH:19][N:18]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c(c1)nc(Cc1ccc(O)cn1)n2CC1CC1
Reactant: CCI
Agent: CO[Na]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-[(5-hydroxy-2-pyridinyl)methyl]-1H-benzimidazole-5-carbonitrile (120 mg, 0.394 mmol) in DMSO (1 mL) was added MeONa (25% in MeOH, 0.47 mmol). After being stirred at room temperature for 30 min, MeOH was removed in vacuo and EtI (0.47 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The solution was diluted with H2O (10 mL), extracted with EtOAc (2×20 mL), washed with H2O (2×10 mL), and lastly dried over MgSO4. The residue obtained after evaporation was purified by silica gel column chromatography to give the pure product as an oil (84 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J=3.0 Hz, 1H), 8.04 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.13 (dd, J=10.0 Hz, J=2.8 Hz, 1H), 4.47 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14–1.08 (m, 1H), 0.60–0.54 (m, 2H), 0.36–0.30 (m, 2H). MS (ES) (M+H)+=333.
Reaction SMILES: O1CCN([CH:7]=[C:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])CC1.[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH2:32])=[NH:31].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]1[NH:32][C:14](=[O:15])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:31]=1
Reactant: CCOC(=O)C(=CN1CCOCC1)C(=O)OCC
Reactant: CC(C)COc1ccccc1NC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Diethyl morpholinomethylenemalonate (20.0 g) is added to a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (16.1 g) and potassium carbonate (21.5 g) in ethanol (40 ml) and water (40 ml), and the mixture is heated with stirring at 60° C. for 3 hours. After the reaction is completed, water (100 ml) is added to the reaction mixture with stirring under water-cooling, and the mixture is acidified to pH 3 with 10% aqueous HCl. The resulting precipitate is collected by filtration and dissolved in chloroform (300 ml). The chloroform layer is washed with water twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (16.0 g). M.p. 175°-177° C.
Reaction SMILES: O[CH2:2][CH:3]([CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]#[N:5].N12CCCN=C1CCCCC2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:2]=[C:3]([CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]#[N:5]
Reactant: CC(C)CC(C)CC(C)C(C#N)CO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C#N)C(C)CC(C)CC(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A 250 ml three-neck round-bottom flask which is dry and is purged with nitrogen is charged in succession with 19.7 g of the cyano alcohol (VII) (0.1 mol), 150 ml of anhydrous methylene chloride, and then 18.26 g (0.11 mol) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The solution is cooled to 0° C. and then 22.05 g (0.105 mol) of trifluoroacetic anhydride are added dropwise, without 5° C. being exceeded in the mass. The resulting solution is stirred at ambient temperature for 16 hours and then hydrolyzed, dried, and concentrated. The residue is distilled under vacuum (6 torr) to give 16 g of unsaturated nitrile (VIII), which distills at 105-108° C. The yield is 89%.