Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Si:17]([O:24][CH2:25][CH:26]=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Si:17]([O:24][CH2:25][CH2:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of benzyl 1-piperazinecarboxylate (1.751 mL, 9.08 mmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (1.209 mL, 9.99 mmol), in MeOH (5 mL) and dichloroethane (5 mL) was stirred for 20 minutes with 4 Å molecular sieves. The mixture was added to a solution of sodium triacetoxyborohydride (4.81 g, 22.70 mmol) in tetrahydrofuran (5 mL) and stirred overnight. The reaction mixture was added to sodium bicarbonate (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were concentrated under reduced pressure, and the residue purified with silica chromatography (EtOAc/MeOH) to give 2.10 g, (61%) of a clear oil. 1H NMR: 7.34 (m, 5H), 5.05 (s, 2H), 3.67 (t, 2H), 3.36 (m, 4H), 2.40 (m, 6H), 0.84 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(CCCCCCl)NCCCO
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCO
Yield: 95.1 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(3-hydroxypropyl)-5-chloropentanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(3-hydroxypropyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (940.0 mg) as a pale yellow oil (yield: 95.1%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:21]([C:19]2[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=2[O:25][CH3:26])(=[O:22])=[O:23])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (1.34 g, 7.6 mmol) in dichloromethane (66 ml) and pyridine (1.6 ml) was treated with 5-chloro-2-methoxy-benzenesulfonyl chloride (1.83 g, 7.6 mmol, 1 equiv.). The mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with water. The organic phase was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, 2.2 g (77% yield). MS (ISP): m/e=382.1 (M+H+.), δH (300 MHz; CDCl3) 7.99 (1H, d), 7.93 (1H, s), 7.61 (1H, d), 7.37 (1H, dd), 7.11 (1H, d), 6.77 (1H, d), 4.04 (2H, t), 3.83 (3H, s), 3.56 (3H, s), 3.02 (2H, t).
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH:30][C:40]([NH:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:41])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)Nc1ccccc1
Reaction time: 4 h
Yield: 25.2 %

Procedure:
A mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxylic acid hydrazide of Example 8 (0.56 g) and phenylisocyanate (0.17 g) in tetrahydrofuran (25 mL) was refluxed under stirring for four hours. After removal of all volatiles at reduced pressure, the residue was treated with water and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and the solution filtered through a short column of Magnesol®. After elution with several additional volumes of dichloromethane, the combined eluate was evaporated to dryness to provide the title compound as a yellow amorphous solid (0.18 g).
Reaction SMILES: C(O)(=O)C.O.[NH2:6][NH2:7].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:21]#[N:22])[CH2:17][C:18](=O)[CH3:19]>C(O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:17]=[C:18]([CH3:19])[N:7]=[N:6][C:21]=1[NH2:22]
Reactant: CC(=O)CC(C#N)c1ccc(C)cc1C
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc(C)nnc2N)c(C)c1

Procedure:
Acetic acid (5 mL) and hydrazine monohydrate (2.52 g, 0.05 mol) were added to a solution of 1-(2,4-dimethylphenyl)-3-oxobutyl cyanide (10.13 g, 0.05 mol) in ethanol (100 mL), and the mixture was heated under reflux for 8 hours. The reaction mixture was evaporated as it was. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine as a crude product.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].C([N:26]1C2C(=CC=C([N+]([O-])=O)C=2)C(C2C=CC(C#N)=CC=2)=C1)(C)C.S(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:26][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[C:10]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)=[CH:11]1
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Agent: O=S([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(N)c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add NaH (98 mg, 2.47 mmol) to 4-(6-nitro-1H-indol-3-yl)-benzonitrile (500 mg, 1.9 mmol) in DMF (10 mL) at 0° C. under N2 and stir for additional 30 min at room temperature. Add excess NH2Cl ether solution prepared according to the procedure described in J. Org. Chem. 2004, 69 (4), 1369, and stir for an hour. Add 10% sodium bisulfite and extract with EtOAc. Wash the EtOAc extracts with 10% sodium bisulfite twice and dry over MgSO4. Evaporate the solvent to give 4-(1-amino-6-nitro-1H-indol-3-yl)-benzonitrile.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=4[O:23][CH:24]([CH2:29][CH2:30][CH3:31])[C:25](=[N:27][OH:28])[NH2:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44](OCC)=[O:45]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=4[O:23][CH:24]([C:25]4[NH:26][C:44](=[O:45])[O:28][N:27]=4)[CH2:29][CH2:30][CH3:31])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)c1noc(=O)[nH]1
Yield: 47.5 %

Procedure:
2-{2-{[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanamide oxime (240 mg) and triethylamine (61 mg) were dissolved in tetrahydrofuran (3 ml). To this solution was added a solution of ethyl chloroformate (65 mg) dissolved in tetrahydrofuran (1 ml) under ice-cooling. The reaction mixture was stirred for fifteen minutes, filtered, and concentrated. The resulting material was dissolved in xylene (4 ml) and 1.8-diazabicyclo[5.4.0]undec-7-ene (152 mg) was added. The mixture was stirred at 50° C. for three hours. The mixture was cooled, diluted with toluene, and washed successively with 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. The crude material was purified on a silica gel column eluting with a mixed solvent of methylene chloride and methanol (1% vol.) to give partially purified product which was again purified on a silica gel column eluting with a mixed solvent of toluene and ethyl acetate (6:1) to give 3-{1-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}butyl}-1,2,4-oxadiazoline-5-one (120 mg).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][S:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH3:20])=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
Phenylmethanesulfonyl chloride (28.1 g, 147.7 mmol) was added into a solution of (S)-1-(4-bromophenyl)ethanamine (28.0 g, 140.7 mmol) and triethylamine (21.3 g, 211.1 mmol) in dichloromethane (400 mL) drop wise at 0° C. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction solution was then washed with dilute aqueous HCl, saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound (35.3 g, 71% yield) as pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[N:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.C(N(CC)CC)C>[CH3:15][S:16]([O:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[N:5]1)(=[O:18])=[O:17]
Reactant: CCOC(=O)c1cnn(CCO)c1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (200 g) in a mixture of methylene chloride (2 l) and triethylamine (210 ml) was added dropwise methanesulfonyl chloride (85.5 ml) under ice-cooling. The mixture was stirred for 1 hour at 3°-5° C. The reaction mixture was poured into ice-water (700 ml). The separated organic layer was washed with 1N hydrochloric acid and water, and dried over magnesium sulfate. The solvent was evaporated to give 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270.8 g) as crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:4]=2[NH:3]1.Br[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:21]3[CH:22]=[C:23]([NH2:24])[CH:25]=[CH:26][CH:27]=3)=[CH:10][C:4]=2[NH:3]1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Temperature: 25 °C
Yield: 15 %

Procedure:
2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid pinacol ester (0.227 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-20% MeOH/CH2Cl2). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.021 g in 15% yield.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=C(S)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:8]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Fc1cccc(S)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2cccc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 3-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C(N/[C:5](=[CH:9]/[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([NH2:20])=[C:12]([Cl:21])[CH:11]=1)/[C:6]([OH:8])=[O:7])(=O)C.Cl.[OH2:23]>CN1C(=O)CCC1>[NH2:20][C:13]1[C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10](/[CH:9]=[C:5](/[OH:23])\[C:6]([OH:8])=[O:7])=[CH:11][C:12]=1[Cl:21]
Reactant: CC(=O)N/C(=C/c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Reactant: O
Agent: Cl
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)cc(/C=C(/O)C(=O)O)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 3 h

Procedure:
51.0 g (158 mmol) (E)-2-acetylamino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acrylic acid, dissolved in 408 ml NMP, were combined with 612 ml aqueous 4-molar hydrochloric acid solution and stirred for 3 hours at a bath temperature of 130° C. stirred. The reaction mixture was cooled and poured onto 2000 ml of water with stirring. The precipitate formed was suction filtered, washed with 400 ml of water, dried overnight at 60° C. and recrystallised from 1000 ml boiling toluene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[S:42][C:43]3[CH2:44][N:45]([CH3:50])[CH2:46][CH2:47][C:48]=3[N:49]=2)[C:26]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:24][N:25]1[C:26](=[O:51])[C:27]([NH:40][C:41]2[S:42][C:43]3[CH2:44][N:45]([CH3:50])[CH2:46][CH2:47][C:48]=3[N:49]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: CN1CCc2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)sc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCc2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4C=O)cn(C)c3=O)sc2C1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (138 mg, 0.40 mmol), 216a (240 mg, 0.60 mmol), PdCl2(dppf) (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate trihydrate (120 mg, 0.80 mmol), water (6 drops), and acetonitrile (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. Then, it was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 216b as a yellow solid (100 mg, 45%). MS-ESI: [M+H]+ 586.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[O:24])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CSC(=O)N1CC(C)(C)SCc1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]-L-cysteine methyl ester (0.5 g) in dimethylformamide (10 ml), carbonyldiimidazole (0.28 g) was added and the mixture was stirred for 2.5 hours at 100°-110° C. 1N hydrochloric acid was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and then saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography and recrystallized from n-hexane--isopropanol to give 0.22 g (40%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1nccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2cn3ccsc3n2)cc1
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a mixture of 2-aminothiazole (H) (23.7 g, 0.23 mol) and 2-bromo-1-(4-fluorophenyl)-ethanone (I) (50 g, 0.23 mol) is added absolute ethanol (600 mL). The reaction is allowed to reflux with vigorous stirring for 16 hours. The reaction mixture is reduced to half its original volume in vacuo. The remaining liquid is poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%). The resulting fine solid is filtered and washed with water. The dark yellow solid so obtained is dried in a vacuum oven at 50° C. to provide 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (J) (43.0 g, 86%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[C:16]([CH3:23])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)=[C:16]([CH3:23])[CH:15]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: Cc1cc(F)ncc1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)ncc1-c1ccc2cc(N)ncc2c1
Yield: 83.5 %

Procedure:
A mixture of 7-bromoisoquinolin-3-amine (410.5 mg; 1.840 mmol), (6-fluoro-4-methyl-3-pyridyl)boronic acid (374.1 mg; 2.414 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (70.4 mg; 0.0994 mmol), potassium carbonate (624.3 mg; 4.517 mmol), dioxane (6.0 mL; 70 mmol) and water (0.6 mL; 30 mmol) was subjected to microwave irradiation at 120° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 20-100% ethyl acetate in dichloromethane) to yield 389.0 mg (83%) of the title compound. LCMS (ESI): M+H=254.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:27][CH3:30])[CH:24]([CH3:25])[CH3:26])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2-methylpropan-1-ol (73.6 mg, 0.173 mmol) in N,N-dimethylformamide (1.0 mL) was added sodium hydride (10.3 mg, 0.260 mmol) at 0° C. After 30 min, to the mixture was added methyl iodide (53.9 μL, 0.865 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hrs. The mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (43.7 mg, 0.0996 mmol, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[SiH](CC)(CC)CC.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cn1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2ccc(F)cc2)cn1
Yield: 43 %

Procedure:
(6-Amino-3-pyridinyl)(4-fluorophenyl)methanone (30 mg, 0.138 mmol) was dissolved in 1 ml of trifluoroacetic acid. 16 l of sulfuric acid (2.2 eq) and 50 l of Et3SiH and stirred at ambient temperature for 4 h in a closed vial. The reaction mixture was poured into water, basified with 2N sodium hydroxide and extracted into methylene chloride. Organic extract was washed with water and brine, concentrated and purified by column chromatography on silica (10 g, EtOAc/hexane 1:1) to give 12 mg of desired product (43% yield).