Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.COCCN(S(F)(F)[F:32])CCOC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:32])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)ccn2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)ccn2)CC1
Temperature: -40 °C

Procedure:
To a solution of tert-butyl 4-(4-chloropyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (C3) (0.600 g, 1.92 mmol) in CH2Cl2 (10 mL) cooled to −78° C. was added bis(2-methyoxyethyl)aminosulfur trifluoride (Deoxofluor, 0.71 mL, 3.8 mmol). The reaction was slowly warmed to −40° C. over 3 h, then quenched with water (5 mL) and warmed to RT. The mixture was extracted with CH2Cl2 (2×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 10-40% ethyl acetate in hexanes to provide tert-butyl 4-(4-chloropyridin-2-yl)-4-fluoropiperidine-1-carboxylate (C4).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4][N:3]=[N:2]1.[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C.O1CCOCC1>[CH3:14][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2cccc(C=O)c2)n1
Temperature: 0 °C

Procedure:
With the exclusion of air, 10.0 g (57.4 mmol) of 3-(tetrazol-5-yl)-benzaldehyde are added to 23.7 g (172 mmol) of potassium carbonate in 120 ml of DMF/dioxane (1:1) in an ice bath. 5.37 ml (86 mmol) of methyl iodide are added dropwise thereto and the reaction mixture is stirred for 2 hours in the ice bath and for 1 hour at RT. The reaction mixture is stirred into 0.5 liter of water, and the crude product is filtered off with suction and washed with water. Dissolution in 0.3 liter of ethyl acetate, washing with brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 3-(2-methyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.47 (hexanelethyl acetate=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(OC[C@@H]2CCCN2)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 71.2 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (80 mg, 0.146 mmol), (S)-2-((4-bromophenoxy)methyl)pyrrolidine (77 mg, 0.3 mmol), 2.0M aqueous potassium carbonate (0.5 mL, 1.0 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (40 mg, 42% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.45 (d, 2H), 6.85 (d, 2H), 4.10 (m, 1H), 3.75 (s, 3H), 3.65 (m, 1H), 3.52 (m, 1H), 3.05 (m, 2H), 2.05 (m, 1H), 1.90 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:18]>CCOCC>[Cl:18][C:1]1[NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 0 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 2-cyano-4-oxo-4-phenylbutanoate (8 g, 34.6 mmol) in Et2O (100 ml) was bubbled HCl gas at 0° C. for 30 min. After reaction mixture was stirred for 1 day at 0° C., the resulting solution was evaporated under reduced pressure. The residue was purified with silica gel column (EtOAc:Hx=1:3) to produce title compound (7.3 g, 84.5%) as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:54]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:59]=[CH:58][C:57]([CH:60]([NH:67][CH3:68])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:59]=[CH:58][C:57]([CH:60]([N:67]([CH3:68])[C:11](=[O:13])[CH2:10][N:6]2[C:5]3[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
[6-Methyl-5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (59 mg, 0.25 mmol) and BOP reagent (133 mg, 0.30 mmol) were dissolved in CH2Cl2 (1 mL), and diisopropylethylamine (32 mg, 0.25 mmol) was added to it. The resulting mixture was stirred at room temperature for 5 min, then 1-(4-biphenylyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (70 mg, 0.25 mmol) was added. Stirring was continued for 16 h and then the mixture was concentrated. The residue was dissolved in CH3OH, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×50 mm, 50 mL/min, A: acetonitrile B: water with NH4OH at pH=10, A: 20% to 70% during 12 min, UV detection at 214 nm) to give 92 mg (74%) of the title compound as a white solid. MS (ES) m/e 500 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]([N:4]2[C:5]3[CH:10]=[C:9]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:31])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: O=C1CCC(c2ccc3c(c2)NCCO3)=NN1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCOc3ccc(C4=NNC(=O)CC4)cc32)cc1OC

Procedure:
6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was dissolved in methylene chloride and 1.1 equivalent of triethylamine. 1.1 equivalent of 3,4-dimethoxybenzoylchloride was added and the mixture heated at reflux for four hours. The solution was washed with sodium bicarbonate solution and then evaporated to dryness. The residue was chromatographed on silica gel eluting with 1:1 ethyl acetate:ethyl ether. The title compound was collected as white needles, mp 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[N:10]O.C(C1NC=CN=1)(C1NC=CN=1)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]=[CH:6][C:7]=1[F:8]
Reactant: ON=Cc1cncc(F)c1Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: N#Cc1cncc(F)c1Cl
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a suspension of 4-chloro-5-fluoro-pyridine-3-carbaldehyde oxime (6.8 g, 39.0 mmol) in dichloromethane (150 ml) was added carbonyl diimidazole (9.5 g, 58.5 mmol). The mixture was then heated at reflux for 30 minutes before cooling to room temperature, before being washed with saturated aqueous sodium bicarbonate followed by water. The organic layer was dried over sodium sulfate and concentrated in vacuo and the resultant residue triturated in diethyl ether/cyclohexane to afford the title compound as a pale yellow solid (4.05 g, 79%). 1H NMR (CDCl3) 8.71 (1H, d, J=0.4 Hz), 8.70 (1H, s).
Reaction SMILES: [C:1]([CH:3]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9])#[N:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:28][OH:29].Cl>C1COCC1.CN(C=O)C.C(=O)([O-])O.[Na+]>[C:1]([CH:3]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:28][OH:29])=[O:9])#[N:2]
Reactant: N#CC(CCCCC(=O)O)c1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC(CCCCC(=O)NO)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
In THF (8.5 ml)-DMF (0.1 ml) was dissolved 6-cyano-6-(1-naphthyl)hexanoic acid (4.0 g) (15 mmol) followed by dropwise addition of oxalyl chloride (3.2 ml) (37.5 mmol) at room temperature. After 15 minutes of stirring, the excess oxalyl chloride was distilled off under reduced pressure. The residue was dissolved in dichloromethane (63 ml) and the solution was added to a solution (63 ml) of hydroxylamine hydrochloride (3.13 g) (45 mmol) in saturated aqueous sodium hydrogen carbonate solution with ice-cooling. The reaction was carried out at room temperature for 2 hours, at the end of which time the reaction mixture was made weakly acidic with concentrated hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (hexane-ethyl acetate=1:9) to provide the title compound (4.08 g) (yield 96.3%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([Cl:13])[CH:3]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH3:24])[CH:18]=[C:17]([CH3:25])[N:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:1][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH3:24])[CH:18]=[C:17]([CH3:25])[N:16]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: COC(=O)Cc1ccc(N)cc1Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(Nc2nc(C)cc(C)c2[N+](=O)[O-])cc1Cl
Temperature: 50 °C
Reaction time: 9 h
Yield: 30.8 %

Procedure:
To a mixture of methyl 2-(4-amino-2-chlorophenyl)acetate (step 4, 2.6 g, 13.0 mmol) and 4,6-Dimethyl-3-nitro-2-pyridine (step 2 of Example 1, 2.4 g, 13.0 mmol) in DMSO was added diisopropylethylamine. The resulting mixture was stirred for 9 h at 50° C. To the mixture was poured into water and extracted with ethyl acetate (3×30 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give a brown oil. This was purified by SiO2 column chromatography with developing hexane/ethyl acetate (10/1) to give 1.4 g (29%) of title compound as yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)C>CCOCC.O>[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=1)[CH3:4]
Reactant: CN(C)CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 2.5 °C

Procedure:
A reaction mixture was prepared containing 15.5 g. of dimethylaminothioacetamide hydrochloride, 20.5 g. of ethyl bromopyruvate and 100 ml. of ethanol. The reaction mixture was heated to refluxing temperature for about four hours after which time the solvent was removed in vacuo in a rotary evaporator. The residue, containing ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate formed in the above reaction, was dissolved in a mixture of ether and water. The aqueous layer was separated. The ether layer was extracted with an equal volume of water and then discarded. The two aqueous layers were combined and washed with ether. The ether layer was again discarded and the aqueous layer cooled to a temperature in the range of 0-5° C. Solid potassium carbonate was added until the aqueous layer gave a basic reaction to litmus. An oil separated comprising ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate free base. The oily layer was extracted with ether and the ether extract separated and dried. The ether was removed by evaporation in vacuo. The resulting residue was purified by gradient high pressure liquid chromatography (silica ethyl acetate). Ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate thus obtained had the following physical characteristics:
Reaction SMILES: C1(S([CH2:9][N:10]2[C:14]([NH:15][C:16](=[O:23])[CH:17](Cl)[CH:18]3[CH2:21][CH2:20][CH2:19]3)=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:12]=[N:11]2)=O)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH:18]1([C:17]2[C:16](=[O:23])[NH:15][C:14]3[N:10]([N:11]=[N:12][C:13]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1c(-c2ccccc2F)nnn1CS(=O)c1ccccc1)C(Cl)C1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a cold (−78° C.), stirred solution of N-[3-benzenesulfinylmethyl-5-(2-fluorophenyl)-3H-1,2,3-triazol-4-yl]-2-chloro-2-cyclobutylacetamide (166 mg. 0.37 mmol) in dry tetrahydrofuran (20 ml) under nitrogen was added a solution of potassium bis(trimethylsilyl)amide (1.8 ml, 0.752 M in toluene, 1.3 mmol) and the reaction stirred for 2 hours. The reaction was allowed to warm to −20° C. and maintained at this temperature for 45 minutes before quenching by careful addition to water (100 ml). The aqueous mixture was stirred for 5 minutes and then acidified with citric acid solution (25 ml, 10% aqueous). The aqueous was extracted with ethyl acetate (2×70 ml) and the combined organic extracts were washed with water (50 l), brine (50 l), dried (Na2SO4) and evaporated in vacuo to approximately 2 ml total volume. The concentrated solution was allowed to stand at room temperature for 16 hours. The solid precipitate thus formed was collected by filtration and washed with diethyl ether to afford 6-cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (45 mg, 43%) as a pale solid which was used in subsequent reactions without further purification. δH (400 MHz, d6-DMSO) 1.78-1.89 (1H, m, CH(CH2)3), 1.93-2.0 4(1H, m, CH(CH2)3), 2.11-2.31 (4H, m, CH(CH2)3), 3.47 (1H, quintet, J=8.6 Hz, CH(CH2)3), 7.30-7.35 (2H, m, ArH, 7.44-7.50 (1H, m, ArH), 7.69 (1H, t, J=7.2 Hz, ArH), 8.82 (1H, s, CH═C.), 12.33 (1H, br s, NH); m/z (ES+) 285 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][N:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[S:14]>>[Br:1][CH2:2][CH2:3][CH2:4][N:9]1[C:10](=[O:13])[C:11](=[O:12])[N:7]([CH3:6])[C:8]1=[S:14]
Reactant: CN1C(=O)C(=O)NC1=S
Reactant: BrCCCBr
Product: CN1C(=O)C(=O)N(CCCBr)C1=S

Procedure:
By the procedure of Example 1(i), 1,3-dibromopropane was reacted with 1-methyl-2-thioxo-4,5-imidazolidinedione to yield 1-(3-bromopropyl)-3-methyl-2-thioxo-4,5-imidazolinedione which, on reaction with thiourea by the procedure of Example 1(ii) gave S-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))propyl]isothiourea hydrobromide. Hydrolysis of the latter compound by the procedure of Example 1(iii) and recrystallisation of the product from water gave the title compound, m.p. 141°-143°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[CH2:17][OH:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-[2-(3-bromophenyl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (400 mg, 1.21 mmol) in methanol (30 mL) was added 4 M HCl in dioxane (2 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration in vacuo, the residue was used for the next step without purification. LCMS (M+H)+ m/z 230 (t=0.78 min.)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]([Cl:21])([O:13][C:14](=O)[O:15]C(Cl)(Cl)Cl)[Cl:12].C.C1(C)C=CC=CC=1>CCCCCC.CCOCC>[Cl:10][C:11]([O:13][C:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:15])([Cl:21])[Cl:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(OC(Cl)(Cl)Cl)n1nnc2ccccc21

Procedure:
A stirred mixture of benzotriazole (3 g), triphosgene (11.22 g), charcoal (1 g) and anhydrous toluene was refluxed overnight and filtered. Evaporation of the filtrate gave an oily solid which was suspended in a mixture of hexane and ether (1:1). Filtration and evaporation of the filtrate gave the titled compound as an oil.
Reaction SMILES: C(O[C:4](=[O:16])[CH:5](Br)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)C.[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19][C:18]1=[S:27]>C(O)C>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[S:27][C:18]3=[N:17][C:26]4[C:21]([CH2:20][N:19]3[C:4]2=[O:16])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Reactant: S=C1NCc2ccccc2N1
Solvent: CCO
Product: O=C1C(c2ccc([N+](=O)[O-])cc2)SC2=Nc3ccccc3CN12
Yield: 88.1 %

Procedure:
A solution of bromo-(4-nitrophenyl)acetic acid ethyl ester (0.92 g, 3.2 mmol) in ethanol (15 ml) was added to a suspension of 3,4-dihydro-1H-quinazoline-2-thione (0.5 g, 3.0 mmol) in ethanol (10 ml) and the resulting mixture was heated at reflux for 3 h. A brown solid was filtered, washed with ethanol, and dried under reduced pressure to yield 0.86 g (88%) of a yellowish solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 4.89 (m, 2H) 5.95 (s, 1H) 7.12 (d, J=7.63 Hz, 1H) 7.17 (t, J=7.48 Hz, 1H) 7.26 (m, 2H) 7.82 (d, J=8.85 Hz, 2H) 8.25 (d, J=8.85 Hz, 2H). MS (ESI) m/z 326 (MH+); HPLC (Column YMC Xterra OSD 4.6×33 mm S 7) rt 1.53 min; Purity (93%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([O:19]C)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:22]>CCOCC>[C:1]1([C:7]2[CH:16]=[C:15]([C:17](=[O:19])[CH3:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]C
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccccc12
Solvent: CCOCC
Product: CC(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
To methyl 2-phenyl-4-quinolinecarboxylate (1 g, 3.80 mmol) in 10 ml ether, at 0° C. was added MeLi (1.4M, 3.0 ml, 4.1 mmol) dropwise over a five minute period. The reaction mixture was stirred at 0° C. for 30 minutes and quenched by the addition of 10 ml of water. The ether layer was separated, dried over sodium sulfate, filtered, concentrated and purified (hexane:EtOAc; 4.5:0.5) to give 0.233 g (23%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCCCNc1ccc(CC(=O)OCC)cc1
Yield: 91.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and butyraldehyde (250 μL, 2.79 mmol) were converted to the title compound (600 mg, 87%). 1H NMR (CDCl3) δ 7.12-7.04 (m, 2H), 6.60-6.52 (m, 2H), 4.14 (q, J=7.0 Hz, 2H), 3.49 (s, 2H), 3.11 (t, J=7.0 Hz, 2H), 1.66-1.50 (m, 2H), 1.50-1.36 (m, 2H), 1.25 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 236.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC[N:34](CC)CC.[NH4+].[Cl-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:26][C@H:27]([C:29]([NH2:34])=[O:30])[CH2:28]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 1 h

Procedure:
A mixture of cis-3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid (Intermediate 36; 100 mg; 0.23 mmol), Et3N (0.13 mL; 0.93 mmol), NH4Cl (24 mg; 0.45 mmol) and HATU (173 mg; 0.45 mmol) in THF (5 mL) was stirred for 1 hour. The reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 98 mg (98%) of the title compound as a white solid, which was used directly without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C.Cl.[NH2:19]O.C[O-].[Na+]>>[OH:3][C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:16][N:19]=1
Reactant: CCOC(=O)C(C(=O)c1cccnc1)C(C)C
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)c1c(O)noc1-c1cccnc1
Yield: 22.7 %

Procedure:
2-Nicotinoylisovaleric acid ethyl ester (0.76 g), hydroxylamine hydrochloride (0.46 g) and sodium methoxide (28% methanol solution, 3.1 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.15 g, 23%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10](/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2cccc(Cl)c2)n1
Product: Cc1cc(Cl)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 130 °C
Yield: 70.9 %

Procedure:
0.246 g (1 mmol) of (E)-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol were treated with 1.83 ml (20 mmol) of POCl3 and subsequently heated at 130° C. for 4.5 hours. The mixture was cooled to RT, concentrated in vacuo and the residue was partitioned between EtOAc, water and saturated KHCO3. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a short silica gel column with CH2Cl2/hexane (3:2) as eluent. Combination of the purified fractions and concentration in vacuo gave 188 mg (71%) of the desired (E)-4-chloro-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidine as a white solid. EI mass spectrum, m/e: 264 (M calculated for C13H10Cl2N2: 264)