Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[CH3:2].O.NN>C(O)COCCO.C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[CH3:2]
Reactant: CCOC(=O)CCCCCC(=O)Cc1ccc(C)cc1C
Agent: NN
Agent: O=S(=O)(O)O
Solvent: OCCOCCO
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCCCc1ccc(C)cc1C
Yield: 61.6 %

Procedure:
12.8 g of 8-(2,4-dimethylphenyl)-7-oxo-octanoic acid ethyl ester [obtained according to (d)] are reduced, analogously to the method described by Huisgen [R. Huisgen et al., Liebigs Ann. 586 (1954), 52] with hydrazine hydrate in diethylene glycol. The isolated reduction product, in 200 ml of ethanol and 5 ml of concentrated sulphuric acid, is heated at the reflux temperature overnight and, after customary working up, gives 7.5 g of 8-(2,4-dimethylphenyl)-octanoic acid ethyl ester as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]2[NH:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[NH2:19][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:25])[CH3:26])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:18][CH:17]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Yield: 103.7 %

Procedure:
tert-Butyl [2-(6-benzyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (13.75 g), 5% platinum on carbon (1.03 g), and acetonitrile (250 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filter pad was rinsed with acetonitrile. The filtrate was concentrated under reduced pressure. Residual water was removed by an azeotrope with toluene. Removal of all volatiles under reduced pressure provided 13.34 g of crude tert-butyl [2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as a brown foam.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:23][CH3:24])=[CH:18][CH:19]=[N:20]3)=[CH:15][CH:14]=2)[S:7]1(=[O:26])=[O:25]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][O:23][C:17]1[C:16]2[C:21](=[CH:22][C:13]([CH2:12][N:8]3[S:7](=[O:26])(=[O:25])[NH:6][C:10](=[O:11])[CH2:9]3)=[CH:14][CH:15]=2)[N:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc4c(OC)ccnc4c3)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccnc2cc(CN3CC(=O)NS3(=O)=O)ccc12

Procedure:
210 mg (459 μmol) of the title D compound, 2-(2,4-dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one are stirred for 30 min in 4 mL of 1:1 TFA/CH2Cl2. The solvent is removed on a rotary evaporator and the residue triturated with 4 mL of 1:1 MeCN/water. This mixture is filtered through a 0.2 micron disk and the solvent is removed. The resulting material is purified by preparative LC/MS, and the collected product fractions are lyophilized to give 5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one: [M−1]−=306.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:34])[CH:15]([NH:20][C:21](=[O:33])[C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:24])[CH3:23])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2.Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.[H-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:34])[C@H:15]([NH:20][C:21](=[O:33])[C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:23])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2
Reactant: BrCc1ccccn1
Reactant: CC(C)CC(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccccn2)C1=O
Reaction time: 2 h

Procedure:
tert-Butyl 1-(1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g) and 2-(bromomethyl)pyridine hydrobromide (553 mg) were sequentially added to N,N-dimethylformaldehyde (7.5 mL), and sodium hydride (174 mg) was added in two portions to the mixture under cooling on ice, followed by stirring for two hours. The resultant mixture was extracted with ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:2), whereby the title compound (393 mg) was yielded.
Reaction SMILES: C(NC1SC(S(NC2C=CC(CC([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29]([CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:30]=3[NH2:31])=O)=CC=2)(=O)=O)=C(C)N=1)(=O)C.[Cl:46][C:47]1[N:51]([CH3:52])[N:50]=[C:49]([CH3:53])[C:48]=1[S:54]([NH:57][C:58]1[CH:59]=[CH:60][C:61]([CH2:64][C:65]([OH:67])=O)=[N:62][CH:63]=1)(=[O:56])=[O:55].NC1C(=O)N(CC2C=CC=CC=2F)C(=O)N(CCCC)C=1N>>[NH2:31][C:30]1[N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:26](=[O:45])[C:25]=1[NH:24][C:65](=[O:67])[CH2:64][C:61]1[CH:60]=[CH:59][C:58]([NH:57][S:54]([C:48]2[C:49]([CH3:53])=[N:50][N:51]([CH3:52])[C:47]=2[Cl:46])(=[O:55])=[O:56])=[CH:63][N:62]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Agent: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NS(=O)(=O)c3c(C)nn(C)c3Cl)cn2)c(=O)n(Cc2ccccc2F)c1=O

Procedure:
Prepared as for 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (example 10, step 1) except using [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid and 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione. N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide was used without purification (91%); LRMS for C27H30ClFN8O5S (M+H)+ at m/z=633/635.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.Cl[C:18]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])=[N:27][C:22]=2[CH:21]=[N:20][N:19]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O.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>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[NH:28][C:26]1[CH:25]=[CH:24][C:23]2[C:18]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])=[N:19][N:20]=[CH:21][C:22]=2[N:27]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1nncc2nc(Nc3ccc(F)cc3F)ccc12
Temperature: 130 °C

Procedure:
A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (252 mg, 1.12 mmol), 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine (300 mg, 1.02 mmol) and tetrakis (36 mg, 31 μmol) in 4.0 mL of dioxane and sodium carbonate (2.0 mL of 1 N solution) was heated in a microwave at 130° C. for 35 min. It was diluted with 10 mL of EtOAc and 2.0 mL water and extracted. An additional extraction with DCM (15 mL) was done. The combined extracts and an insoluble tan solid were dried over MgSO4. Filtration through a sintered glass frit washing with 1:1 MeOH:DCM resulted in complete solubilization of the tan solid. The solution was concentrated and washed with Et2O (2×15 mL), EtOAc (15 mL) and hexanes (2×15 mL) to afford a tan amorphous solid which was purified on the ISCO to afford the title compound as a yellow amorphous solid. MS (ESI, pos.ion) m/z: M+1=354.0
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(#N)C.O1CCCC1>[CH2:11]([S:8]([NH:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)NCc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
N-(4-Aminobenzyl)ethanesulfonamide (504 mg, 2.35 mmol) was dissolved in acetonitrile (3 mL) and tetrahydrofuran (4 mL). The reaction mixture was added pyridine (0.23 mL, 2.78 mmol) and phenyl chloroformate (0.31 mL, 2.43 mmol) and stirred at room temperature for 3 h under nitrogen atmosphere. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 4-(ethylsulfonamidomethyl)phenylcarbamate (697 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH2:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=[CH:23][N:22]=[N:21]1.[K].[CH3:26][N:27](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH2:12])[CH2:10][N:22]2[CH:23]=[N:27][CH:26]=[N:21]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [K]
Product: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1

Procedure:
A mixture of 10.2 g (0.040 ) of crude 2-(4-fluorophenyl)-2-[1-(4-fluorophenyl)ethenyl]oxirane and 7.0 g (0.065 mol) of potassium triazole in 60 mL of DMF was heated at 60° overnight, then cooled and poured into 100 mL of 1:1 Et2O/hexanes. After washing the organic layer three times with H2O and once with brine, a precipitate formed in the organic layer. Filtering gave 4.8 g of a brown solid which was recrystallized from 500 mL of cyclohexane to yield 2.5 g of a light-tan powder, mp 136°-137° C.: NMR (CDCl3)δ1.7 (br s, OH); 4.7 (q, 2H); 5.3 (s, 1H); 5.5 (s, 1H); 6.8-7.1 (m, 6H); 7.4 (m, 2H); 7.8 (s, 1H); 7.9 (s, 1H); IR (nujol) 3120 (br), 1900, 1600, 1505, 1220, 1139, 835 cm-1.
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:6](=[O:16])[N:5]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:4]=2[N:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C.O>O1CCCC1>[NH2:1][C:2]1[N:10]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:6](=[O:16])[N:5]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc2c(c(=O)n(CC3CC3)c(=O)n2CC2CC2)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
8-Amino-1,3-di(cyclopropylmethyl)xanthine (2.7 g, 10 mmol), 4-nitrobenzenesulphonyl chloride (5.5 g, 25 mmol) and triethylamine (3 ml, 20 mmol) were stirred together in tetrahydrofuran (THF) (40 ml) at ambient temperature for 24 hr. After adding to water (100 ml) the mixture was extracted into ethyl acetate (150 ml) and the organic solution dried (MgSO4) and evaporated. Chromatography of the residue on silica, (hexane/acetone gradient) gave 8-amino- 1,3-di(cyclopropylmethyl)-7-(4-nitrobenzenesulphonyl)xanthine followed by 1,3-di(cyclopropylmethyl)-8di(cyclopropylmethyl)-8-di(4-nitrobenzenesulphonyl)aminoxanthine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:21]([CH3:22])[CH3:20])=[O:17])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)O
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
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[4-(benzyloxy)-2-methylphenyl]acetic acid (1.1 g, 4.29 mmol) was dissolved in DMF (5 ml) and dimethylamine (6.44 ml, 12.88 mmol), DIEA (2.25 ml, 12.88 mmol), and HATU (3.26 g, 5.58 mmol) added. The mixture was stirred at RT for overnight. The residue was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. to afford the title compound. LC/MS (m/z): 284 (M+H)+.
Reaction SMILES: [C@H]1(N)[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].[C:9]([O-:12])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][CH2:20][CH2:19]2.BrC1C(C=O)=CC=NC=1>O1CCOCC1.[Cu]I.O>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:3]1[CH:4]=[C:5]([CH:9]=[O:12])[CH:6]=[N:7][CH:2]=1)[CH2:20][CH2:19]2
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=Cc1ccncc1Br
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 348.8 %

Procedure:
CuI (190 mg, 1 mmol), (1S,2S)-cyclohexane-1,2-diamine (228 mg, 2 mmol) and Cs2CO3 (6.5 g, 20 mmol) were added to a solution of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (1.82 g, 10 mmol, intermediate A-2) and 5-bromo-pyridine-4-carbaldehyde (3.72 g, 20 mmol) in dioxane (15 mL). The reaction mixture was heated to 150° C. using microwave for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (2.0 g, 70%) as brown oil. MS: 287.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[C:14]([CH3:18])=[C:15]([CH3:17])[NH:16][C:9]=23)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Cl)=[CH:48][CH:47]=1>O1CCCC1>[ClH:45].[Cl:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][N:16]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[C:14]([CH3:18])=[C:15]2[CH3:17])=[CH:48][CH:47]=1
Reactant: Cc1[nH]c2c(OCc3ccc(F)cc3)ccnc2c1C
Reactant: ClCc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccc(Cl)cc2)c2c(OCc3ccc(F)cc3)ccnc12
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (25 mg, 0.105 mmol) prepared in Step 1, potassium tert-butoxide (13.6 mg, 0.163 mmol), and a catalytic amount of 18-crown-6 were added to anhydrous tetrahydrofuran (2 ml). 4-Chlorobenzyl chloride (0.089 ml, 0.160 mmol) was added to the reaction mixture, which was then stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol=10/10/1, (v/v/v)), dissolved in ethyl acetate (1 ml), and then saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (6.9 mg, 15.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:4]([F:9])[CH:3]=1
Reactant: O=C1CCC1
Reactant: Fc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCC1
Reaction time: 0.25 h

Procedure:
A 100 mL 3-neck round bottom flask was charged with 4-bromo-2-fluoro-1-iodobenzene (1000 mg, 3.32 mmol) and diethyl ether (30 mL). The solution was cooled to −78°G, and n-butyllithium (1.329 mL, 3.32 mmol) was added dropwise, keeping the temperature below −68° C. After stirring for 15 min, cyclobutanone (0.249 mL, 3.32 mmol) was added dropwise, keeping temperature below −68° C. The solution was stirred at −78° C. for 15 min. The reaction was then quenched by the addition of saturated ammonium chloride (25 mL). The layers were separated, and the organic was washed with water (1×10 mL) and brine (1×10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2 gel), eluting with 3% ethyl-acetate/hexanes to give the desired product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.69 (m, 1H), 1.91-2.05 (m, 1H), 2.19-2.28 (m, 2H), 2.46-2.55 (m, 2H), 5.59 (s, 1H), 7.33-7.40 (m, 2H), 7.44-7.48 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[CH3:9][S:10]([NH2:13])(=[O:12])=[O:11].[OH-].[Na+]>CC(C)=O.O>[CH3:9][S:10]([NH:13][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])(=[O:12])=[O:11]
Reactant: FC(F)(F)CN=C=S
Reactant: CS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=S)NCC(F)(F)F
Yield: 19.2 %

Procedure:
A solution of 2,2,2-trifluoroethylisothiocyanate (1.4 g.) in acetone (20 ml.) was added to a solution of methanesulphonamide (0.95 g.) and sodium hydroxide (0.44 g.) in water (10 ml.) and the mixture stirred and heated under reflux for 18 hours, and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts dried and evaporated to dryness. The residue was triturated with acetonitrile and filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, and the solution extracted with aqueous sodium bicarbonate solution. The extract was neutralised with N hydrochloric acid and the mixture extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to dryness to give 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.45 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:5][CH:4]=1.C=O.[C:19]([BH3-])#N.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:19])=[CH:15][CH:16]=1
Reactant: COc1ccc(CSC[C@@H]2CCCN2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CSC[C@@H]2CCCN2C)cc1
Yield: 41.7 %

Procedure:
The procedure described in preparation 5-(4) was repeated, but using 2 g of (2S)-2-(4-methoxybenzylthio-methyl)pyrrolidine, 35% formalin and 848 mg of sodium cyanoborohydride in the presence of 44 ml of acetonitrile, to afford 883 mg of the title compound as an oil.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9](Cl)=[O:10].[CH3:19][C:20]([NH:29][CH2:30][C:31]([CH3:33])=[CH2:32])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21].O>ClCCl>[CH3:21][C:20]([N:29]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:9](=[O:10])[CH:8]([Br:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:19]
Reactant: O=C(Cl)C(Br)c1ccccc1F
Reactant: C=C(C)CNC(C)(C)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=C(C)CN(C(=O)C(Br)c1ccccc1F)C(C)(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
In 30 ml of dichloromethane containing 2.8 g of pyridine, 4.0 g of 2-bromo-2-(2-fluorophenyl)acetyl chloride were added dropwise to 2.5 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-2-methyl-2-propenylamine at 10° to 15° C. After stirring at room temperature for 1 hour, the solution was poured into water, and extraction was then made with dichloromethane. The resultant extract was washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. After concentration, column chromatography was done to obtain 2.0 g of the desired N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(2-methyl-2-propenyl)-2-bromo-2-(2-fluorophenyl)acetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: CN(C)CCCN
Reactant: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.39 g) was added to 4-chloro-N-methyl-3-nitrobenzamide (1.46 g) and the mixture was stirred for 5 hours at 120° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (1.88 g) as yellow solid.