Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:11]([N:13]([CH2:18][CH2:19]OS(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:11]([CH3:12])[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:18][CH2:19][N:25]1[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]([C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)N(CCOS(C)(=O)=O)S(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1[C@H](COCc2ccccc2)N(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Reaction time: 3.5 h
Yield: 90.3 %

Procedure:
A solution of (2R,3S)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-methanesulfonyloxyethyl)-N-methanesulfonylamino]butanol (1.1 g) in dry THF (15 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 80.1 mg) in dry THF (8 ml) at 4° C. over 15 minutes. The mixture was stirred at the same temperature for 3.5 hours and then poured into saturated aqueous NH4Cl solution. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 40% and 50%) to give 0.80 g of (2R,3S)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methylpiperazine as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:10]=2[F:9])[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(F)c1F
Solvent: CCO
Product: Fc1cccc(Nc2cc(Cl)ncn2)c1F
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To 14 ml of ethanol were added 2.2 g of 4,6-dichloropyrimidine and 2.3 g of 2,3-difluoroaniline, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 3.5 g of 4-chloro-6-(2,3-difluoroanilino)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of ethyl 4-bromo-2-chlorobenzoate (1.00 g, 3.79 mmol), tributyl(vinyl)tin (2.41 g, 7.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (439 mg, 0.38 mmol) in DMF (15 mL) was stirred at 100° C. for 1 hr. After cooling, the mixture was diluted with water (150 mL), and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=20:1) to give the title compound (820 mg, 100%) as a colorless oil.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.21 min; [M+H]+=497.1.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[C:6]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=1.[OH-].[K+]>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])#[CH:11]
Reactant: COCCCOc1cc(C(=O)OC)ccc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(C(=O)O)cc1OCCCOC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(3-methoxy-propoxy)-4-trimethylsilanylethynyl-benzoic acid methyl ester (16.49 mmol) in MeOH (40 mL) is added KOH (1 N, 24.7 mL, 24.7 mmol). The resulting mixture is stirred at RT for 15 h and concentrated under reduced pressure. The residue was taken up in HCl (2 N, 100 mL) and extracted with AcOEt (100 mL×3). The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title as a yellow oil which is used without further purification in the next step. MS (FAB): 235.0 [M+H]+. 1H-NMR (CDCl3, 300 MHz): δ=2.15 (p, 2H), 3.38 (s, 3H), 3.41 (s, 1H), 3.62 (t, 2H), 4.22 (t, 2H), 7.5 (d, 1H), 7.65 (s, 1H), 7.68 (d, 1H) ppm.
Reaction SMILES: C[C@H](N)[C@H](O)C1C=CC=CC=1.Cl.COCCOCCOCCOC.CSC.C(SCC)C.ClC1C=C(Cl)C=CC=1/C=C(/N1C=NC=N1)\C(=O)C(C)(C)C.[CH:54]([C:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:58])([CH3:56])[CH3:55]>ClCCCl.ClC1C=CC=CC=1.CN(C)C=O>[C:59]1([CH:57]([OH:58])[CH:54]([CH3:55])[CH3:56])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: CC(C)C(=O)c1ccccc1
Agent: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: C[C@H](N)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CSC
Solvent: COCCOCCOCCOC
Solvent: ClCCCl
Product: CC(C)C(O)c1ccccc1
Reaction time: 18.5 h
Yield: 97.2 %

Procedure:
The same procedure as in Example 1 was repeated except that (+)-norephedrine hydrochloride was replaced by (-)-norephedrine hydrochloride, triglyme was replaced by 0.4 ml of dimethylformamide, dimethyl sulfide was replaced by diethyl sulfide, monochlorobenzene was replaced by 1,2-dichloroethane, (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one was replaced by 0.27 g (1.85 mmoles) of phenyl isopropyl ketone, and the reduction reaction was conducted for 18.5 hours, to obtain 0.27 g of crude (-)-phenylisobutyl alcohol.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23].ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl.C(OCC)(=O)C>[OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21]([CH3:22])=[O:29])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc([C@H]2Cc3cc(SC)ccc3NC(=O)[C@H]2O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2Cc3cc(S(C)=O)ccc3NC(=O)[C@H]2O)cc1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of (cis)-1,3,4,5-Tetrahydro-3-hydroxy-7-methylthio-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (1.0 g, 3.04 mmol) in dry methylene chloride (30 ml) at 5° C. was treated with m-chloroperoxybenzoic acid (0.615 g, 3.04 mmol). After 30 minutes, the reaction was complete and the reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, water, and brine. The organic layer was filtered and concentrated in vacuo to give a solid residue (1.02×g). Trituration with hot ethyl acetate, cooling and filtration afforded the product (600 mg), m.p. 214°14 216° C. The mother liquors were concentrated in vacuo and chromatographed on LPS-1 silica (methylene chloride/methanol). The product fractions were combined and concentrated in vacuo, and the residue crystallized from ethyl acetate to give an additional 200 mg of product.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: Nc1nc2cc(F)ccc2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-fluorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-fluorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:25]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=1)[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (2.35 g) was dissolved in CH2Cl2 (60 ml) and TFA (20 ml) was added. After stirring for 1 h at RT, the mixture was concentrated in vacuo to yield 2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oil that solidified upon standing. The material was used as is without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[OH:45][CH2:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58](O)=[O:59])=[CH:52]2.CCN(C(C)C)C(C)C>O.CCOC(C)=O.CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:58]([C:53]2[NH:54][C:55]3[C:51]([CH:52]=2)=[CH:50][C:49]([O:48][CH2:47][CH2:46][OH:45])=[CH:57][CH:56]=3)=[O:59])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1cc2cc(OCCO)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(OCCO)ccc4[nH]3)c2F)c1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
HATU (0.026 g, 0.069 mmol) was added to a DMF (1 mL) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.022 g, 0.069 mmol), 5-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.015 g, 0.069 mmol) and DIPEA (0.012 mL, 0.069 mmol). The reaction mixture was stirred for 2 h, poured into EtOAc and water and the layers separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. The residue was dissolved in MeOH and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.013 g, 37%) as a white solid 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 8.96 (t, 1H), 7.80 (s, 1H), 7.44-7.54 (m, 3H), 7.37 (t, 1H), 7.28 (d, 1H), 7.05 (s, 2H), 6.83 (dd, 1H), 4.80 (t, 1H), 4.54 (d, 2H), 3.94 (t, 2H), 3.70 (q, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=1>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][C:23]=1[N+:31]([O-:33])=[O:32])(=[O:28])=[O:29])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCCNS(=O)(=O)c1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069–12802.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then 4-methyl-2-nitro-benzenesulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give desired product (1.60 g, 92%) as a solid. 1H-NMR (500 MHz; DMSO-d6) δ 7.87 (d, 1H), 7.81 (s, 1H), 7.66 (d, 1H), 4.06 (q, 2H), 3.24 (s, 2H), 2.91 (t, 2H), 2.57 (t, 2H), 2.44 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:12]1[CH2:16][CH2:15][O:14][C:13]1=[O:17].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1OCCC1Br
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
Cesium fluoride (7.6 g) was added to a solution of 4-chlorophenol (1.29 g) in dimethylformamide (35 mL) and the mixture was stirred at 100° C. for 5 min. 3-bromodihydrofuran-2(3H)-one (3.3 g) was added and the reaction mixture was heated to 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with EtOAc. The aqueous layer was extracted with ethylacetate. The organic layers were washed with water, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (1.17 g; 55%). MS (ESI): m/z=212 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C)C=O>[Cl:37][CH2:36][CH2:35][CH2:34][CH2:33][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 120.9 %

Procedure:
A mixture of 0.185 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 1.5 mL of dimethylformamide, 0.813 g (2.5 mmole) of cesium carbonate and 0.173 mL (1.5 mmole) of 1-bromo-4-chloro-butane was heated at 100 degrees for 1 hour. The mixture was concentrated under reduced pressure, diluted with water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.279 g of 2-[6-(4-chloro-butoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.37a) as a light brown solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of carbazole (3.34 g, 20 mmol) in DMF (80 mL) at 0° C. was added NaH (0.72 g, 30 mmol). After heating to 80° C. for 1.5 h, 1-chloro-2-(2-methoxyethoxy)ethane (3.31 g, 24 mmol) was added dropwise. The resulting mixture was kept at 80° C. overnight. After cooling down to 0° C., the reaction mixture was carefully quenched with water and extracted with ethyl acetate three times. The combined organic phase was washed with water and brine. Then the organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluent (EA:PE=1:3) to afford alkylated carbazole 1a (4.46 g) as brown oil in 83% yield. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=7.6 Hz, 2H), 7.46 (m, 4H), 7.23 (m, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.86 (t, J=6.4 Hz, 2H), 3.52 (m, 2H), 3.42 (m, 2H), 3.31 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.5, 125.6, 122.8, 120.2, 118.9, 108.7, 71.8, 70.7, 69.1, 59.0, 43.0. MS (FAB) m/z Calcd for C17H19NO2 269.1 Found 269.2 [M]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O.ClCCl>[C:24]([NH:6][C@@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([O:3][CH3:2])=[O:15])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Yield: 90.6 %

Procedure:
300 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol) and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 21.88 g of dodecanoyl chloride (0.1 mol) was slowly added, following by stirring for 3˜4 hours. 200 ml of water was added to the reacted material, followed by extraction with 500 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by separation by column chromatograph using hexane and ethyl acetate (Hex:EA=2:1), thereby obtaining a white solid (34.2 g, 90.5% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].Br[Zn][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.CN1CCCC1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH3:2]
Reactant: Br[Zn]c1cccs1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CCc1c(-c2cccs2)[nH]c(C=O)c1C(=O)OC
Temperature: 100 °C

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. To a solution of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (0.123 g, 0.40 mmol) and bromo(thien-2-yl)zinc (0.1374 g, 0.60 mmol) in THF (2.0 mL) was added Pd(Pt-Bu3)2 (0.0123 g, 0.02 mmol) and N-methylpyrrolidine (2.0 mL). The reaction was deoxygenated by bubbling argon through the solution prior to being heated to 100° C. and refluxed for 4 h under argon. After cooling to ambient temperature, the reaction was filtered through a pad of silica gel and concentrated. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.14 (s, 1H); 7.42 (d, J=5.1 Hz, 1H); 7.24 (d, J=3.7 Hz, 1H); 7.14 (dd, J=3.7, 4.7 Hz, 1H); 3.94 (s, 3H); 2.94 (q, J=7.4 Hz, 2H); 1.24 (t, J=7.4 Hz, 3H). HRMS (ES) exact mass calculated C13H14NO3S (M+H): 264.0689. Found 264.0688
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])=[O:8].[CH2:23]([Li])CCC.CI.O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][S:7]([CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:23])(=[O:9])=[O:8]
Reactant: [Li]CCCC
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CNS(=O)(=O)C(C)c2ccccc2)c(OC)c1
Reaction time: 0.08 h

Procedure:
Under inert gas, 375 mg of N-(2,4-dimethoxybenzyl)-C-phenylmethanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 1.46 ml of a 1.6 N butyllithium solution in hexane were added dropwise and the mixture was left to stir for 5 minutes. After the addition of 166 mg of methyl iodide, the reaction mixture was allowed to come to room temperature. The reaction solution was admixed with 50 ml of water and 50 ml of ethyl acetate, and the aqueous phase was reextracted with 50 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (334 mg) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1(C)C=CC=CC=1>[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1Cl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cccnc1N1CCCCC1=O
Reaction time: 5 h

Procedure:
To a suspension of 1.1 g of 60% sodium hydride in 10 ml of toluene is added 5 g of 2-oxopiperidine, followed by addition of 6.4 g of 2-chloro-3-(4-chlorobenzoyl)pyridine. The mixture is stirred at 90°-100° C. for 5 hours. After water is poured into the reaction mixture, the solvent of the toluene layer is distilled off. The residue is recrystallized from methanol to give 2-(2-oxopiperidino)-3-(4-chlorobenzoyl)pyridine, m.p. 154°-156° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)#[N:5]
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Reactant: CCN
Product: CCNC(=NCCSCc1cnccn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2-(2-pyrazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.