Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]([CH3:23])[CH2:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:24]#[N:25])[CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH2:12][N:13]4[CH2:18][C@H:17]([C:19]([F:20])([F:21])[F:22])[O:16][C@H:15]([CH3:23])[CH2:14]4)=[CH:9][CH:10]=3)[N:5]=[C:4]([C:24]#[N:25])[CH:3]=2)[CH:29]=[N:28]1
Reactant: C[C@@H]1CN(Cc2ccc3c(Cl)cc(C#N)nc3c2)C[C@H](C(F)(F)F)O1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc3c(-c4cnn(C)c4)cc(C#N)nc3c2)C[C@H](C(F)(F)F)O1
Temperature: 70 °C
Yield: 67.4 %

Procedure:
4-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-7, 859 mg, 2.323 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (725 mg, 3.48 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), and X-Phos (111 mg, 0.232 mmol) were combined in THF (10 ml). To this was added 1M K3PO4 (7 ml, 7.00 mmol). The mixture was degassed (3× pump/N2) then heated to 70° C. overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (100 g, 50% EtOAc/hexanes) to afford 4-(methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-8, 650 mg, 67%) as a white solid. 1H NMR (399 MHz, CDCl3): δ 8.22 (d, J=8.7 Hz, 1H); 8.10 (s, 1H); 7.86 (s, 1H); 7.78 (s, 1H); 7.71 (dd, J=8.7, 1.7 Hz, 1H); 7.63 (s, 1H); 4.07 (m, 3H); 3.78 (m, 3H); 2.92 (d, J=11.0 Hz, 1H); 2.75 (d, J=11.4 Hz, 1H); 2.22 (t, J=10.8 Hz, 1H); 1.97 (t, J=10.8 Hz, 1H); 1.20 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=2)=[N:5][CH:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:8]=1)#[N:2].Cl>O1CCOCC1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[C:18]1[CH:36]=[CH:37][C:15]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:6][N:5]=2)=[CH:16][CH:17]=1
Reactant: CNCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)c(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3N)cc2)c(C#N)c1

Procedure:
t-Butyl (2-{[4-(3-cyano-5-{[2-(methylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (465 mg, 0.93 mmol, prepared as described in Method 30), 1,4-dioxane (3.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (3.5 ml) were stirred at ambient temperature for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:42](=[O:49])[C:43]5[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=5)[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)N(C(=O)c1cccnc1)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 29.4 %

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol), triethylamine (228 μL, 1.6 mmol) and nicotinoyl chloride hydrochloride (146 mg, 0.2 mmol) in CHCl3 (10 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (35 mg, 28.9%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]=1[F:35])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]([F:35])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Yield: 100.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate (520 mg, 0.934 mmol) prepared in Example 11a, trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (427 mg, 99%) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([N:6]1[C:7]2[C:3](=[C:2]([I:1])[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=2)[CH:4]=[CH:5]1)[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1cc(I)c2cc[nH]c2c1
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Temperature: 80 °C

Procedure:
To a mixture of methyl 4-iodo-1H-indole-6-carboxylate (1.0 g) in DMF (10 mL) was added potassium hydroxide (0.392 g) and 1-iodobutane (0.8 mL). The mixture was heated to 80° C. for 18 h. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 20% ethyl acetate in hexanes as eluent to give 0.73 g of the title compound: 1H NMR (CDCl3) δ 0.940, 1.32, 1.81, 3.95, 4.15, 6.45, 7.31, 8.09, 8.18.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C([O:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[C:42]([F:47])[CH:41]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:43]2[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][C:42]=2[F:47])=[CH:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1)(COC(C)=O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixed solution of N-[1,1-bis(acetoxymethyl)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl]acetamide (867 mg) of Reference Example 9, 1-benzyloxy-4-bromo-3-fluorobenzene (674 mg), sodium hydrogen carbonate (1.01 g) and tetrakistriphenylphosphine palladium (46 mg) in 1,2-dimethoxyethane (15 mL)-water (5 mL) was stirred at 65° C. for 5 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in methanol (30 mL) were added palladium carbon (10%, 0.3 g) and ammonium formate (517 mg), and the mixture was stirred at room temperature for 6 hr under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.56 g) as white amorphous crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([CH3:22])=[CH:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[C:13]([CH3:22])=[CH:12][C:11]4=[O:23])[CH2:4][CH2:3]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
To 1.5 mL of dichloromethane solution containing 6.0 mg of 1-(2-(4-aminocyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one, 10 mg of molecular sieves 3A, 3.4 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 1.6 μL of acetic acid were added at room temperature, and stirred at the same temperature for 1.5 hours. To the reaction mixture, 6.0 mg of sodium triacetoxyborohydride was added, and stirred at the same temperature for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[eluent; chloroform:methanol=0:1], to give 5.5 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1>C(O)C.O.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCOCC2)c(C(=O)O)c1

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 87 ml morpholine. The temperature of the thick mixture rose to 75° C. After being stirred at reflux temperature for five hours, the mixture was poured into ice water, made acidic with concentrated HCl, filtered, dried and recrystallized from ethanol to give 20.3 grams 2-morpholino-5-nitrobenzoic acid. m.p. = 168°-170° C. The nitro compound was reduced catalytically in ethanol-water (3:1) with 5% palladium on carbon catalyst to give 5-amino-2-morpholinobenzoic acid. m.p. = 307°-308° C.
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[CH:7]=[CH:8]/[C:9]2[N:17]=[C:16]3[N:11]([C:12]([CH3:19])=[N:13][CH:14]=[C:15]3[CH3:18])[N:10]=2)[N:4]([CH3:20])[N:3]=1.C1([O-])C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:71]1[CH2:74][CH2:73][CH2:72]1>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.C(Cl)(Cl)Cl.[Pd].[Pd]>[N:71]1([C:2]2[N:6]=[C:5](/[CH:7]=[CH:8]/[C:9]3[N:17]=[C:16]4[N:11]([C:12]([CH3:19])=[N:13][CH:14]=[C:15]4[CH3:18])[N:10]=3)[N:4]([CH3:20])[N:3]=2)[CH2:74][CH2:73][CH2:72]1
Reactant: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Reactant: C1CNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCC4)nn3C)nc12
Yield: 63.9 %

Procedure:
A solution of (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (150 mg, 449 μmol, Eq: 1.00) in dioxane (210.4 ml) was purged with argon, then sodium phenolate (78.2 mg, 673 μmol, Eq: 1.5), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-phos) (20.8 mg, 35.9 μmol, Eq: 0.08), tris(dibenzylideneacetone)-dipalladium chloroform complex/Pd2(dba)3CHCl3 (18.6 mg, 18.0 μmol, Eq: 0.04) and azetidine (76.9 mg, 90.5 μl, 1.35 mmol, Eq: 3) were added. The vial was capped and irradiated at 140° C. for 40 minutes in a microwave oven. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate/methanol 0-10% as eluent affording 2-[(E)-2-(5-azetidin-1-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (89 mg, 63.9%) as light yellow solid. MS: m/z=311.5 (M+H+), MP: 210.4° C.
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][N:19]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:22][S:21][C:20]1=[N:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[O:39][CH3:40])[CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14])=O)(C)(C)C.Cl>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([N:31]=[C:20]2[N:19]([CH2:18][CH2:17][CH2:16][NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][S:21]2)=[C:33]([O:39][CH3:40])[CH:34]=1
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CCOCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCCOCC(=O)O

Procedure:
The compound (750 mg) obtained in the above (2) was treated in a similar manner to in Example 9 (2) to give the title compound (579 mg) as hydrochloride.
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O.P(Br)(Br)([Br:25])=O>>[Br:25][C:13]1[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=1
Reactant: Cc1ccccc1-n1c(O)nc2ccc(OS(C)(=O)=O)nc21
Reactant: O=P(Br)(Br)Br
Product: Cc1ccccc1-n1c(Br)nc2ccc(O)nc21

Procedure:
From 2-hydroxy-3-o-tolyl-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate and phosphoryl tribromide, prepared in a similar manner as the one described in Example 1.136, the title compound was obtained. LCMS m/z=304.20 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 2.05 (s, 3H), 6.7 (d, J=8.6 Hz, 1H), 7.33 (d, J=7.8, 1H), 7.42-7.47 (m, 1H), 7.48-7.53 (m, 2H), 7.94 (d, J=8.7, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: CCI
Reactant: Cc1cccc(Cl)c1NC(=S)NCC(N)=O
Agent: Cl
Product: CCSC1=NCC(=O)N1c1c(C)cccc1Cl
Yield: 36.4 %

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.9 g of 2-[3-(2-chloro-6-methylphenyl)-thioureido]-acetamide, and 18.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as the monohydrochloride as a light yellow solid (4.9 g), m.p. 152°-154° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S. HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 46.99; H, 4.60; N, 9.16. Mass spectrum (+FAB, [M+H]+) m/z 269/271 1H-NMR (DMSO-d6 ; 400 MHz) δ8.28 (broad s, 2H), 7.51 (m, 1H), 7.44 (t, 1H), 7.39 (m, 1H), 4.51 (q, 2H), 3.12 (q, 2H), 2.17 (s, 3H), and 1.27 ppm (t, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]4O[CH:25]=[N:24][CH:23]4S(C4C=CC(C)=CC=4)(=O)=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:37]>CCO>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[N:37]=[CH:25][NH:24][CH:23]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cc1
Reactant: N
Solvent: CCO
Product: c1nc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c[nH]1
Temperature: 110 °C
Yield: 12 %

Procedure:
The 5-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazole (500 mg) was dissolved in EtOH saturated with ammonia (7 ml) before heating in a bomb at 110° C. for 18 hours. The solvent was removed in vacuo and the residue was taken up in DCM (10 ml) and washed with saturated sodium bicarbonate solution (15 ml), followed by brine (15 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo, before purifying by column chromatography, eluting with a gradient of DCM:MeOH:NH3 (from 99:1:0.1 to 90:10:1), but this failed to separate the product from a close running impurity. The residue was therefore purified using column chromatography a second time, eluting with an isocratic solution of cyclohexane:DCM:Et2O:MeOH:NH3 (10:5:3:2:0.2) to afford the title compound as a colourless solid (70 mg, 12%). 1H NMR (400 MHz, CDCl3) δ 1.8 (m, 4H), 1.93-2.05 (m, 2H), 2.24-2.39 (m, 4H), 2.57 (m, 4H), 2.63 (t, 2H), 3.67 (m, 2H), 3.79 (m, 2H), 4.00 (t, 2H), 6.77 (s, 1H), 6.81 (d, 2H), 7.18 (d, 2H), 7.38 (s, 1H). LRMS ESI+ m/z 356 [MH]+, 354 [M−H+]−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[NH4+].[Cl-].O>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cn2nccc(N3CCOCC3)c2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn2nccc(N3CCOCC3)c2n1
Reaction time: 1 h

Procedure:
A stirred solution of compound 5c (14 g, 51 mmol) in THF (400 mL) was cooled in an ice-water bath under an argon atmosphere and treated with lithium aluminium hydride (1M in THF, 51 mL, 51 mmol) dropwise. After 1 h, saturated NH4Cl solution (20 mL) was added slowly to quench the reaction, followed by 200 mL of water. The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give compound 5d as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.98 (d, J=5.6 Hz, 1H), 7.77 (s, 1H), 6.05 (d, J=5.9 Hz, 1H), 4.81 (s, 2H), 3.91 (s, 8H), 2.71 (br. s., 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[O:23][CH2:22][CH2:21][NH:20][CH2:19]1.O>CS(C)=O>[CH3:17][CH:18]1[CH2:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:21][CH2:22][O:23]1
Reactant: CC1CNCCO1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(c2ccc(N)cc2)CCO1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (5.64 g, 40.0 mmol) and potassium carbonate (11.1 g, 80.0 mmol) in DMSO (30 mL) was added 2-methylmorpholine (4.05 g, 40.0 mmol), then the mixture was heated at 100° C. for 4 hours. This solution was poured on to water (300 mL) and extracted with EA (3×100 mL). The combined organic phase was washed with brine and dried. Filtered and Pd/C (1.0 g) was added to the filtrate, charged with H2, and stirred at room temperature overnight. The catalyst was filtered and the filtrate was concentrated to give product as a light red solid. MS (m/z): 193 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC=CC=1>CC(O)=O.[Fe]>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(N)c1F
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of methyl 2-fluoro-3,5-dinitrobenzoate (D137) (24.4 g, 0.1 mol, 1 equiv) in AcOH (1 l) was added iron (27.5 g, 0.5 mol, 5 equiv) and the resulting suspension was vigorously stirred for 1 h. The temperature was kept below 35° C. by small amount of cooling using an ice bath during that period. Toluene (200 ml) was added and the suspension filtered through a pad of celite. The remaining solution was concentrated in vacuo and the residue partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the aqueous phase was extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (17 g, 79%) as a yellow solid which was used in the next step without further purification. [M−H]−=212.9, RT=2.68 min.
Reaction SMILES: CSC.B.O=[C:6]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:8]=2[NH:7]1.CO>C1COCC1>[O:10]1[CH2:11][CH2:6][NH:7][C:8]2[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:9]1=2
Reactant: COC(=O)Cc1ccc2c(c1)NC(=O)CO2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)NCCO2
Temperature: 25 °C
Yield: 62 %

Procedure:
Borane dimethylsulfide solution (0.3 ml, 94% in THF) was added at room temperature to a solution of the product from stage 1 (2.7 mmol) in dry THF (14 ml), and the mixture was refluxed for 2 h. Hydrolysis with methanol (1 ml) was carried out, followed by refluxing for a further 15 min. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane). Yield: 62%
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[OH-].[Na+].[CH2:27]=O>C(O)=O>[Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:27])[CH2:8][CH2:7]2
Reactant: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1Br
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(C)CC3)cc1Br

Procedure:
A solution of N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide (0.12 g) in 37% aqueous formaldehyde (0.63 ml) and formic acid (0.34 ml) and stirred at 80° C. for 3 h. Solid sodium hydroxide was added to neutralise the solution and the aqueous phase extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and solvent removed in vacuo to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.[C:16]([NH:19]C1C=CC(Br)=C(C=1)C(O)=O)(=[O:18])[CH3:17].BrC1C=C(OC)C(OC)=CC=1C(O)=O>>[C:16]([NH:19][C:10]1[CH:2]=[CH:1][C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: COc1cc(Br)c(C(=O)O)cc1OC
Product: CC(=O)Nc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 5-acetamido-2-bromobenzoic acid for 2-bromo-4,5-dimethoxybenzoic acid. MS (ESI): mass calculated for C11H10N4O3, 246.22; m/z found 247.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.09 (t, J=2.8 Hz, 1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd, J=2.5, 1.3 Hz, 3H).