Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1.O>C(#N)C>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A solution of methanesulfonylchloride (47.1 mL, 0.61 mol) in acetonitrile (160 mL) was added over 40 min to a solution of 4-nitroaniline (80.0 g, 0.58 mol) and pyridine (70.2 mL, 0.87 mol) in acetonitrile (400 mL) at 25° C. The mixture was stirred at 25° C. for 19 h, and then water (800 mL) was added. The resulting suspension was stirred at 25° C. for 30 min, and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (2×150 mL) and air-dried overnight to afford the desired product, N-(4-nitro-phenyl)-methanesulfonamide (111.4 g, 0.52 mol, 89% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.17 (3H, s), 7.35 (2H, d, J=9.4 Hz), 8.20 (2H, d, J=9.1 Hz), 10.69 (1H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:44])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A solution of triphenylphosphine (281 mg, 1.07 numol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (190.4 mg, 1.07 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (220 mg, 0.63 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (189 mg, 1.89 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide (79 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C20H23ClN6OS (M+) 430.1343, found 430.1343.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:10]=[C:9]([CH2:26]O)[N:8]=1)([OH:3])=[O:2].O=S(Cl)[Cl:30]>C1(C)C=CC=CC=1>[ClH:30].[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:10]=[C:9]([CH2:26][Cl:30])[N:8]=1)([OH:3])=[O:2]
Reactant: COc1ccc(CCCCOc2ccc(CO)nc2/C=C/CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCOc2ccc(CCl)nc2/C=C/CC(=O)O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-hydroxymethylpyridine (1.00 g, 2.69 mmol) was added to a cooled (0° C.) solution of SOCl2 (1.96 mL, 26.9 mmol) in anhydrous toluene (20 mL) under an argon atmosphere. The cooling bath was removed and the reaction was stirred at room temperature for 4.5 h. The solvent and excess SOCl2 were evaporated. The resulting crude product (tan solid) was used without further purification. This material served as the starting material for the preparation of the compounds set out in the following examples.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].C(#N)C.[OH-].[Na+]>O>[CH2:2]([O:4][C:5]([CH2:6][NH:7][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][C:23]=2[Cl:33])[CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10])=[O:8])[CH3:3]
Reactant: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CNC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 95.7 %

Procedure:
7 g of aminoacetic acid ethyl ester chloride, 20.7 g of 2-nitro-5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-benzoic acid chloride and 180 ml of acetonitrile were initially introduced into the reaction vessel. 4 g of sodium hydroxide, dissolved in 10 ml of water, were added dropwise at -10° to -5° C. The reaction mixture was then poured onto water and adjusted to pH 10 and the crystalline product was filtered off. 23 g (95% of theory) of 5-(2,6-dichoro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid (ethoxycarbonylmethyl)-amide with a melting point of 146° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:29]1CCCC1.O>O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19](=[O:29])[NH2:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Nc3ccccn3)s2)C1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Temperature: 150 °C

Procedure:
A solution of {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (455 mg, 1.14 mmol) in 10:1 v/v tetrahydrofuran/water (16.5 mL total volume) was degassed by bubbling in argon for 10 minutes with stiffing. Hydrido-(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (CAS number 173416-05-2) (78 mg, 183 μmol) was added and the mixture was heated to 150° C. by microwave for 45 minutes. The reaction mixture was cooled to ambient temperature, poured into water (150 mL) and extracted with 1:1 v/v tetrahydrofuran/ethyl acetate (4×50 mL), the combined organic extracts were washed with brine (2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a yellow solid. The crude product was purified by chromatography using silica gel gradient eluted from 30% up to 70% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to obtain {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester as an off white solid (362 mg, 76%). LC/MS: m/z calculated for C19H26N6O3S ([M−H]−): 417.5. Found: 417.4 (negative mode electrospray ionization).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1.C([O-])(=O)C.[Na+]>O>[C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: NC1Cc2ccc(O)c(O)c2C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1Cc2ccc(O)c(O)c2C1
Reaction time: 4 h

Procedure:
Acetic anhydride is added to a mixture of 2-amino-4,5-dihydroxyindane [Cannon, J. G., et al., J. Med. Chem. 27, 922(1984)] in water containing sodium acetate. The mixture is chilled and stirred in ice for 4 hours followed by filtration to give N-acetyl-2-amino-4,5-dihydroxyindane. Benzylbromide, powdered potassium carbonate and acetone is added to the isolated N-acetyl-2-amino-4,5-dihydroxyindane and the mixture is stirred for 18 hours. The reaction mixture is poured into water, extracted and evaporated in vacuo to give N-acetyl-2-amino-4,5-dibenzyloxyindane. Hydrolysis with ethanolic sodium hydroxide gives 2-amino-4,5-dibenzyloxyindane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][O:44][CH2:45][C:46]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])=[O:47]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol), N-ethyldiisopropylamine (0.22 ml, 1.278 mmol) and methoxyacetyl chloride (0.067 ml, 0.639 mmol) in dichloromethane (3 ml) was stirred at 23° C. for 16 h. Diluted with dichloromethane, washed with water, dried the organic layer over MgSO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc, followed by trituration with diethyl ether to give the title compound (46 mg, 13%) as a white solid. MS (ISP) 542.7 [(M+H)+]; mp 188° C.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Reactant: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F

Procedure:
Formula 203 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; Rc is 3-Fluoro-4-methyl-phenyl-; W and Z are —N═; X and Y are —C═: To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) is added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution is stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer is extracted with dichloromethane (5 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (10-20% ethyl acetate/hexanes) to give (±)-N{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[O:5]([CH2:12][CH2:13][CH2:14]Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[O:5]([CH2:12][CH2:13][CH2:14][S:3][CH2:1][CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC[S-]
Reactant: BrCCCOc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCSCCCOc1ccccc1

Procedure:
Sodium ethanethiolate (6 mmol, 0.5 g) and 3-phenoxypropyl bromide (5 mmol, 1.1 g) in ethanol were refluxed overnight. After removal of solvent, Ether was added, washed with H20 and evaporated to give 3-phenoxypropylethyl sulfide. It was treated with 1 equivalent of acrylic acid in acetone in the presence of 4 equivalents of 12 N HCl under N2 at room temperature overnight and then at 50° C. for 3 h, affording 3-(S-ethyl-3-phenoxypropylsulfoniumyl)propionic acid chloride as a white powder. It was then subjected to the general procedure 1 to give compound 573 as a white powder (0.58 g, 25% overall yield). Anal. (C14H22Na2O8P2S.0.5 H2O) C, H.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.S(Cl)(Cl)=O.[CH2:17](Cl)Cl.O>CO>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: ClCCl
Reactant: Cc1cc(C(=O)O)c(O)cc1Br
Solvent: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(Br)cc1O
Temperature: 50 °C

Procedure:
To a solution of 4-bromo-2-hydroxy-5-methylbenzoic acid (may be prepared as described in Description 13; 1.47 g, 6.36 mmol) in methanol (15 ml) was added thionyl chloride (0.93 ml, 12.72 mmol). The reaction was heated at 50° C. for 72 hours, then DCM (20 ml) and water (10 ml) were added. The organic layer was separated and washed with saturated NaHCO3 solution (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 1.2 g.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:11].[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:36])[C:33](O)=[O:34])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([OH:36])[C:33]([N:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH2:21][CH2:20][C:17]2[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc2c(c1)CCCC2
Product: O=C([C@@H](O)c1ccc(F)cc1)N(CCc1ccc(C(F)(F)F)nc1)c1ccc2c(c1)CCCC2

Procedure:
In analogy to example 47 (steps 3 & 4), 5,6,7,8-Tetrahydro-naphthalen-2-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-Fluoro-phenyl)-oxo-acetic acid were successively coupled then reduced to give after chiral chromatography (+ve rotation) the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)#N.[OH-].[K+].[C:22]([OH:25])(=[O:24])[CH3:23]>OCC(CO)O.O>[C:22]([C:23]1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)([OH:25])=[O:24]
Reactant: CC(=O)O
Reactant: N#Cc1cc2ccncc2c2sc3ccccc3c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCC(O)CO
Product: O=C(O)c1cc2ccncc2c2sc3ccccc3c12

Procedure:
One hundred thirty mg (0.5 mM) of 6-cyanobenzothieno[3,2-h]isoquinoline (4), prepared in Example 1, was suspended in a hot solution of 168 mg (3 mM) KOH in 1 ml glycerine. The reaction mixture was stirred and heated at 160° C.-170° C. overnight. The resulting yellow solution was cooled, diluted with water and made slightly acidic with glacial acetic acid. A yellow precipitate was collected, washed with water, and air dried to yield 120 mg of product. This initial product was recrystallized from a mixture of DMSO and water to give 78 mg product, mp greater than about 305° C. This then was dried at 80° C./0.2 mm overnight, and characterized as compound 6 using I.R. and mass spectrometry.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:11]([N:18]1[CH:22]=[C:21]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cnn(Cc3ccccc3)c2)ccc1F
Temperature: 110 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (736 mg, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (174 mg, 0.248 mmol), and potassium carbonate (1.36 g, 9.84 mmol) were combined in a sealed vial with dioxane (10 mL) and water (1 mL) under an inert atmosphere of nitrogen, and the mixture was heated to 110° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 290.0 (M+H)+.
Reaction SMILES: Cl[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.[Na+].[I-].[CH3:19][NH2:20]>>[CH3:19][NH:20][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(CCCl)CC1
Reactant: CN
Agent: [I-]
Agent: [Na+]
Product: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Into a 50-mL sealed tube, was placed tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (300 mg, 1.21 mmol, 1.00 equiv), methanamine (in ethanol) (10 mL), NaI (100 mg). The resulting solution was stirred for 12 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 3 mL of water. The pH value of the solution was adjusted to 7-8 with sodium bicarbonate (5%). The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×3 mL of water and 1×3 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 180 mg (crude) of tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate as brown oil
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCN2CCOCC2)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
A solution of 3-bromo-N-{5-[2-(4-fluoro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide (20 mg, 0.046 mmol) and morpholine (8 μL, 0.092 mmol,) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as a pale solid. Anal. RP-HPLC: tR=13.3 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >93%). 1H-NMR (CD3OD) δ: 2.66 (s, 3H, CH3), 3.23 (m, 2H, CH2), 3.33 (m, 2H, CH2), 3.41 (m, 4H, CH2), 3.87 (m, 2H, CH2), 4.13 (m, 2H, CH2), 7.04-7.09 (m, 3H, pyrimidinyl-H & Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 443.3 (C21H23FN6O2S requires 442.5).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.CNCC1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:32]2[CH2:33][CH2:38][CH2:37][CH2:36]2)=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][SH:42])([CH3:36])([CH3:35])[CH3:34]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:42][CH2:41][CH2:40][NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:43])[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Reactant: CC(C)(C)OC(=O)NCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (118 mg, 0.38 mmol) obtained in Example 1-2 and potassium carbonate (212 mg, 1.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (1.0 ml) and (2-mercaptoethyl)carbamic acid tert-butyl ester (0.25 ml, 1.5 mmol) were added thereto. The mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous sodium bicarbonate solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2) to yield 5-[2-amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (143 mg) as a yellow oily material.