Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[C:14]([Br:28])[C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1
Reactant: BrBr
Reactant: Cc1cc(Cl)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The solution of 12.5 g (0.043 mol) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-5-chloropyrazole in the mixed solvent made of 100 ml of chloroform and 100 ml of acetic acid was added with 3.9 g (0.047 mol) of sodium acetate, followed by 7.2 g (0.045 mol) of bromine at 10° C. After stirred at the same temperature for 2 hours, the reaction mixture was poured into ice water and the chloroform layer was separated. The chloroform layer was washed with an aqueous sodium bicarbonate and water and concentrated to obtain 13.0 g of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4-bromo-5-chloropyrazole as pale yellow crystals, melting point: 135° to 137° C. in yield of 82%.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:25]([O:24][C:22]([NH:21][CH2:20][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH2:19][NH:11][CH2:12]2)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc2c1CNC2
Reaction time: 72 h
Yield: 78.4 %

Procedure:
3.44 g of 2-benzyloxycarbonyl-4-(tertbutyloxycarbonylaminomethyl)isoindoline was dissolved in 50 ml of methanol. 200 mg of 10% palladium on carbon was added to it and the mixture was stirred under hydrogen gas stream for 3 days. After removing the catalyst by filtration, the filtrate was concentrated and the residue was recrystallized from ether to give 1.75 g of 4-(tertbutyloxycarbonylaminomethyl)isoindoline.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2.31 g, 10.03 mmol, 1.00 equiv) in dichloromethane (20 mL) and a solution of thionyl chloride (1.5 mL, 2.00 equiv) in dichloromethane (3 mL) was added dropwise under ice-bath. The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×25 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×15 mL of sodium bicarbonate aq. and 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.16 g (46%) of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate as a off-white solid
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Reactant: COC(=O)c1cccnc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncccc3C(=O)OC)C[C@H]2OC)nc1Cl
Yield: 81.3 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (62.51 mg, 0.19 mmol), methyl 2-fluoropyridine-3-carboxylate (68 mg, 0.39 mmol) and diisopropylethylamine (75 mg, 0.58 mmol), to obtain 65.2 mg of the title compound as a yellow brown oily substance (80%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:15][C:11]1([C:3]2[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][CH:2]=2)[CH2:14][O:13][CH2:12]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2Br)COC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(c2ccc(N)cc2)COC1
Temperature: 25 °C

Procedure:
To a refluxing solution of 3-(2-bromo-4-nitrophenyl)-3-methyloxetane (68 mg, 0.2499 mmol) in ethanol (5 mL) was added ammonium formate (68 mg, 1.078 mmol) followed by the addition of Pd/C (32 mg, 0.3007 mmol). The reaction mixture was refluxed for an additional 5 minutes, cooled to room temperature and filtered through a plug of celite. The solvent was evaporated to get 4-(3-methyloxetan-3-yl)aniline. 1H NMR (400 MHz, DMSO-d6) δ 6.93-6.90 (m, 2H), 6.56 (d, J=8.5 Hz, 2H), 4.70 (d, J=5.4 Hz, 2H), 4.45 (d, J=5.6 Hz, 2H), 1.55 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]#[N:36]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:28][C:27]=1[C:35]#[N:36]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1cc(B(O)O)ccc1Cl
Product: N#Cc1cc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)ccc1Cl
Yield: 18.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-chloro-3-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-3′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (18 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 1H), 8.44-8.51 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 2.3 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[CH2:34][CH2:35][OH:36])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[CH2:34][CH:35]=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To a solution of oxalyl chloride (0.62 g, 5 mmol) in CH2Cl2 (20 mL) at −50° C. was added DMSO (0.85 g, 11 mmol, in solution of 5 mL of CH2Cl2) over 2 minutes. 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxyethyl)piperazine (1.85 g, 4.5 mmol, in solution of 5 mL of CH2Cl2) was added. The resulting mixture was stirred at −50° C. for 15 minutes, then triethylamine (2.3 g, 22 mmol) was added. After 5 minutes at −50° C., the mixture was gradually warmed to ambient temperature. At that time the mixture was diluted with CH2Cl2 and washed with water, then brine. The organic layer was then dried over MgSO4 and concentrated in vacuo to afford 1.7 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((formyl)methyl)piperazine as a yellow oil; NMR (CDCl3) 9.8 (d, 1) 7.3 (m, 4), 7.0 (m, 4), 4.6 (m, 3), 3.8-3.2 (m, 7), 2.7-2.2 (m, 4) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:24][CH3:25])[CH3:27])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: CCNC
Product: CCN(C)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and ethyl-methyl-amine. Brown foam. MS (ESI): 375.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>ClCCl>[Cl:22][CH2:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=1
Reactant: CSc1ncc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(CCl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (0.7813 g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0° C.) was added triethylamine (0.836 mL, 8.2 mmol) followed by the addition of methanesulfonyl chloride (0.465 mL, 6.0 mmol). The reaction mixture stirred at 0° C. under a nitrogen atmosphere for 30 minutes then at room temperature for 3.5 hours. The reaction was quenched with sodium bicarbonate (5%, 100 mL)) and extracted with dichloromethane (50 mL). The organic extracts were concentrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane to afford the desired compound (0.720 g, 82%) as a white solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 175.0106 (M+H C6H7N2ClS requires 175.0091).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)c1ccc(Cl)cc1
Product: O=C(O)CCC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
U.S. Pat. No. 5,117,054 describes a process wherein p-chloroacetophenone is reacted with succinic anhydride to form 4-chloro-γ,ε-dioxo-benzenehexanoic acid which is reacted with acetic anhydride or acetyl chloride to yield 5-[2-(4-chlorophenyl)-2-oxoethylidene]dihydro-2(3H)-furanone. This compound is then added to a mixture of N-methylhydroxylamine hydrochloride and an amine base such as triethylamine, Hunig's base, pyridine or lutidine and a solvent such as methylene chloride or chloroform to form 4-chloro-N-hydroxy-N-methyl-γ,ε-dioxo-benzenehexanamide which is combined with 4-methoxyphenyl hydrazine hydrochloride, an amine base as described above in an alcoholic solvent such as methanol, ethanol or propanol.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=[O:8])[CH2:3][CH2:4][C:5]#[N:6].[BH4-].[Na+].ClCCl.C(OCC)(=O)C>CO.OP(O)(O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>[CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[CH2:3][CH2:4][C:5]#[N:6]
Reactant: CC(C)(C=O)CCC#N
Agent: O=[Mo](=O)=O
Agent: O=P(O)(O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CO)CCC#N
Reaction time: 0.29 h

Procedure:
To a solution of 47 g (0.376 mmol) of 4,4-dimethyl-5-oxovaleronitrile in 350 mL of methanol, cooled to 0° C. (ice bath), was added, with vigorous stirring and over 15-20 min., 7.9 g (0.209 mmol; 2.22 hydride equiv.) of NaBH4. After the addition was completed, the solution was stirred an additional 30 min. at 0° C. before removing the solvent in vacuo (aspirator). To the residue was added CH2Cl2 followed by careful addition of H2O, and finally 1.2N HCl until pH=1-2 was obtained. The layers were separated and the aqueous one extracted twice (CH2Cl2), saturated with NaCl and extracted again three times with CH2Cl2. After drying the combined organic layers over Na2SO4 and removing the solvent under vacuum (aspirator) 47.7 g (95%) of the title compound, sufficiently pure for the next step, was obtained as a faint yellow oil. TLC: (Silica) Rf =0.26 (ethyl acetate dichloromethane 1:9), detection with molybdophosphoric acid (yellow spot on blue-green).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20]([CH2:22][C@@H:23]1[CH2:27][CH2:26][C@H:25]([O:28][C:29](=[O:31])[CH3:30])[CH2:24]1)=[O:21]>>[C:29]([O:28][C@@H:25]1[CH2:26][CH2:27][C@H:23]([CH2:22][C:20]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:21])[CH2:24]1)(=[O:31])[CH3:30]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(=O)O[C@H]1CC[C@@H](CC(=O)Cl)C1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and (rac)-(cis)-acetic acid 3-chlorocarbonylmethyl-cyclopentyl ester, (rac)-(cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide was obtained. Separation by preparative chiral HPLC (Chiralpack AD, eluent heptane/isopropanol 85:15) afforded the tide compound as later eluting isomer. Light yellow crystals (4% yield). MS: m/e=434(M+H+), mp 172-173° C.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:21][C:20]=3[Cl:30])=[C:14]([F:31])[CH:13]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=3[Cl:30])=[C:14]([F:31])[CH:13]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2c(F)cc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2cc(F)c(-c3ccc(CC(=O)O)cc3Cl)c(F)c2)nc1C(N)=O
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
Powdered potassium hydroxide (111 mg, 1.98 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′,6′-difluorobiphenyl-4-yl)acetate (Intermediate 2-1; 295 mg, 0.66 mmol) in tert-butanol (10 mL) at 50° C. The resulting solution was stirred at 50° C. for 45 minutes, 2M HCl (2 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water (50 mL) and air dried to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′,6′-difluorobiphenyl-4-yl)acetic acid (220 mg, 77%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc2ccccc12

Procedure:
Example 31 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanatonaphthalene (19.6 μl) to give the title compound (0.0304 g). LC-MS (System A): Rt 2.43 mins, Mass Spectrum m/z 444 [MH+].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:15]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)s1
Temperature: 55 °C
Yield: 99 %

Procedure:
To a solution of 5-chloro-2-thiophenecarboxylic acid (20 g, 123 mmoles) in MeOH (200 mL) was added conc. H2SO4 (5 mL). After heating to 55° C. for 12 h, the reaction solution was concentrated and diluted with DCM (250 mL). The DCM solution was washed with aqueous NaHCO3, then H2O and dried over Na2SO4. Concentration under vacuum gave the title compound as a yellow oil (21.5 g, 99%): LCMS (ES) m/z 178 (M+H)+.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([N+:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:24])[CH3:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(Cl)(Cl)Cl>[Br-].C([N+](CCCCCCCCCC)(C)C)CCCCCCCCC.CS(C)=O>[C:1]([O-:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH2:25]([N+:22]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:24])[CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: O=C([O-])/C=C/c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Didecyldimethylammonium bromide (0.001 mol) was dissolved in 50 mL of hot distilled water. trans-Cinnamic acid (0.001 mol) was added to the didecyldimethylammonium solution. The reaction solution was stirred at 90° C. for 4 h. The reaction solution was cooled to room temperature and then 60 mL of chloroform was added. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a wax was obtained in 93% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=54-55° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:45])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH3:44])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:45])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH3:44])[N:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (135 mg, 0.5 mmol) and 3-[3-(6-methyl-2-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K48) (171 mg, 0.5 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (82 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=O)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=[S:48])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=O)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Solvent: Cc1ccccc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of compound 11-4 (560 mg, 1 mmole), anhydrous toluene (10 mL) and Lawesson's reagent (820 mg, 2 mmole) was refluxed for 4 hrs. Toluene was removed by evaporation. To the residue methanol (20 mL) was added, stirred for few minutes at room temperature and the product was collected by filtration and dried to give 500 mg of the title compound. MS 576 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[CH:9][N:8]=[C:7]([NH:20][CH3:21])[N:6]=2)[CH2:3][CH2:2]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O>[CH:22]1([NH:28][C:13]2[N:12]=[C:11]([C:10]3[C:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)=[N:6][C:7]([NH:20][CH3:21])=[N:8][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Solvent: CS(C)=O
Product: CNc1ncc(-c2ccnc(NC3CCCCC3)n2)c(CC2CC2)n1
Temperature: 160 °C
Yield: 69.8 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (50 mg, 0.165 mmol) in DMSO (1 mL), cyclohexylamine (94 μL, 0.824 mmol) was added, and the reaction was heated in the microwave at 160° C. for 10 minutes. The crude reaction was purified by reverse-phase HPLC [30-100% organic phase with 3% n-propanol modifier over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain the pure desired product as a white solid (39.0 mg, 69.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.04-0.20 (m, 2H) 0.37 (d, J=7.58 Hz, 2H) 0.99-1.19 (m, 2H) 1.19-1.36 (m, 4H) 1.59 (d, J=11.62 Hz, 1H) 1.65-1.80 (m, 2H) 1.88 (d, J=8.59 Hz, 2H) 2.72-2.90 (m, 5H) 3.63-3.80 (m, 1H) 6.68 (d, J=5.05 Hz, 1H) 6.96 (d, J=8.08 Hz, 1H) 7.29 (br. s., 1H) 8.24 (d, J=5.05 Hz, 1H) 8.36 (br. s., 1H). HRMS (ES+) for C19H26N6.H+ [MH+]: calcd, 339.2297; found, 339.2312. UV-LC: 100% UV purity at 254/214 nm; tR=6.70 minutes over 7.75 minutes.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12]1)([O-])=O>Cl.CO.[Fe]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]2([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccccc21
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccccc21

Procedure:
3.76 g of iron powder is added portionwise to a rapidly stirred ice cold slurry of 7.66 g of 1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]hydrochloride of Example 38 in 11.8 ml of concentrated hydrochloric acid and 300 ml of methanol. After heating at reflux for 3 hours, the reaction mixture (at room temperature) is filtered, made basic using 10% aqueous sodium hydroxide and extracted with chloroform. The organic phase is filtered through a pad of celite on a sintered glass funnel and the filtrate is washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4.50 g of the crude free base of the product. Conversion to the hydrochloric acid salt with dichloromethane-ether/ethereal hydrochloric acid and two recrystallizations from hot isopropanol-methanol affords 1-(2-aminophenyl)spiro[indoline-3,4'-piperidine]dihydrochloride, mp 282.5° C., dec.